Impact of Artificial Liver on the Levels of Regulatory Factors of Transdifferentiation in Acute-on-Chronic Liver Failure

Impact of Artificial Liver on the Levels of Regulatory Factors of Transdifferentiation in Acute-on-Chronic Liver Failure | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Impact of Artificial Liver on the Levels of Regulatory Factors of Transdifferentiation in Acute-on-Chronic Liver Failure Shuhan Yang, Xuhong Yang, Bo Qin, Fan Yang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8843627/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract BACKGROUND Acute-on-chronic liver failure (ACLF) is a severe liver disease. Artificial liver based on plasma exchange (PE) has undergone continuous innovation, particularly through the integration of the dual plasma molecular adsorption system (DPMAS), which has been widely validated clinically. Current research on artificial liver primarily focuses on the dynamic changes in inflammatory mediators and metabolites. However, there is limited study on the mechanism of mesenchymal stem cells differentiating into liver cells, specifically the level of transdifferentiation regulatory factors. AIM To investigate the potential and differences during liver cell regeneration in patients with ACLF receiving different modes of artificial liver. METHODS 90 patients with ACLF were divided into three groups: the control group (n = 30), the PE group (n = 30), and the DPMAS + PE group (n = 30). We compared changes in the levels of three regulatory factors of transdifferentiation—hepatocyte growth factor (HGF), oncostatin M (OSM), and fibroblast growth factor-4 (FGF-4)—before and after treatment in the three groups. RESULTS Compared to before treatment, both the PE group and the DPMAS + PE group showed a significant increase in HGF levels (P PE group > control group (P < 0.05). CONCLUSION Artificial liver therapy can aid in regenerating and recovering liver cells by increasing HGF levels. DPMAS + PE demonstrates better performance in this regard compared to PE alone. Trial registration Chinese Clinical Trial Registry, ChiCTR2500098113, retrospectively registered on 3 March 2025. Artificial liver Acute-on-chronic liver failure Plasma exchange Dual plasma molecular adsorption system Mesenchymal stem cells Regulatory factor of transdifferentiation Figures Figure 1 Figure 2 INTRODUCTION Acute-on-chronic liver failure (ACLF) is a severe condition characterized by the sudden deterioration of liver function in patients with underlying chronic liver disease. In China, the primary cause of ACLF is hepatitis B virus infection[ 1 ]. One important treatment for liver failure is the use of artificial liver therapy. In recent years, the artificial liver has experienced ongoing innovations based on plasma exchange (PE), particularly through the integration of the dual plasma molecular adsorption system (DPMAS), which has been extensively validated in clinical practice. Current research in artificial liver therapy primarily focuses on the dynamic changes of inflammatory mediators and metabolites within the liver microenvironment[ 2 ]. However, there is limited literature on the role of mesenchymal stem cells (MSCs) in hepatocyte regeneration. Studies suggest that MSCs can migrate to damaged areas and transdifferentiate into hepatocytes[ 3 , 4 ]. This process depends on the support of the liver microenvironment, with regulatory factor of transdifferentiation such as hepatocyte growth factor (HGF), oncostatin M (OSM), and fibroblast growth factor 4 (FGF-4) playing crucial roles in MSCs' transdifferentiation into hepatocytes[ 5 , 6 ]. This study aims to explore the potential and mechanisms of MSCs' transdifferentiation during liver cell regeneration by assessing the levels of these regulatory factors before and after artificial liver treatment. MATERIALS AND METHODS General information This study followed the Chinese Clinical Practice Guidelines and received approval from the Ethical Committee of the First Affiliated Hospital of Chongqing Medical University (approval number:20226701). All patients provided written informed consent before treatment and agreed to participate in the study. This randomized controlled trial included 90 patients admitted to the internal medicine department of the First Affiliated Hospital of Chongqing Medical University from October 2022 to October 2023. Patients were evaluated based on age, gender, classification, biochemical indicators, and complications, and were randomly divided into three groups according to the principle of "minimum imbalance index allocation": the control group (n = 30), the PE group (n = 30), and the DPMAS + PE group (n = 30). Randomization and Blinding Participants were randomly assigned to the control, PE, or DPMAS + PE groups using a computer-assisted minimization method based on the minimum imbalance index allocation principle to ensure balanced baseline characteristics among groups. The allocation sequence was generated by an independent statistician prior to patient enrollment. To maintain allocation concealment, group assignments were implemented by a research coordinator who was not involved in patient recruitment or outcome assessment. Due to the nature of the artificial liver interventions, blinding of participants and treating clinicians was not feasible. However, laboratory personnel and data analysts were blinded to treatment allocation. Diagnostic,inclusion,and exclusion criteria The inclusion criteria for this study are derived from the "Guidelines for the Diagnosis and Treatment of Liver Failure," established by the Infectious Diseases and Hepatology Branch of the Chinese Medical Association in 2018. These guidelines classify liver failure into four stages: pre-stage, early-stage, mid-stage, and late-stage. Acute-on-chronic liver failure (ACLF) is defined as a syndrome presenting with jaundice and coagulation disorders, accompanied by complications such as hepatic encephalopathy, ascites, infections, and hepatorenal syndrome, all precipitated by various factors within the context of chronic liver disease. Jaundice manifests rapidly and progresses, with serum total bilirubin (TB) levels reaching ten times or more above the upper limit of normal (ULN) or increasing by 17.1 µmol/L or more per day. Additionally, signs of bleeding are evident, with prothrombin activity (PTA) ≤ 40% (or an international normalized ratio [INR] ≥ 1.5). The inclusion criteria for this study specifically target patients with early to mid-stage ACLF attributable to hepatitis B. In contrast, the exclusion criteria encompass individuals aged 70 years, late-stage pregnancy, late-stage acute-on-chronic liver failure (i.e., PTA ≤ 20% or INR ≥ 2.6, or the presence of two or more complications or extrahepatic organ failure), concurrent infections with other viral hepatitis strains (such as HCV, HIV, etc .), liver failure resulting from alternative etiologies (such as alcoholic liver disease autoimmune liver disease, etc .), and other relative contraindications as delineated in the 2022 "Expert Consensus on the Clinical Application of Artificial Liver Blood Purification Technology" (including active bleeding or disseminated intravascular coagulation, hemodynamic instability, unstable periods of cardiovascular or cerebral infarction, and severe allergies to plasma, heparin, protamine, etc .). Research methods All patients received comprehensive internal medicine treatment, which included antioxidants, hepatocyte membrane protectants, anti-inflammatory agents for the liver, medications to alleviate intrahepatic cholestasis, drugs to enhance hepatic microcirculation, and supportive treatments such as plasma and albumin. Complications were also prevented and managed effectively, with all patients diagnosed with hepatitis B receiving nucleoside analogs antiviral therapy. The PE group utilized a novel membrane selective plasma separator, Evacure-4A (Kawasaki, Japan), which operated at a blood flow rate of 90–120 ml/min, with 2000 ml of fresh plasma exchanged during each session. The DPMAS + PE group underwent DPMAS followed by PE. For DPMAS, a sequential application of an anion exchange resin adsorber BS330 (Zhuhai Jianfan) and a neutral resin hemoperfusion column HA330-Ⅱ (Zhuhai Jianfan) was employed. The initial treatment for both the PE and DPMAS + PE groups was completed within 3 days of admission (no later than 1 week), with no more than two treatments administered per week post-admission. Blood samples from the three groups were collected at two time points: upon admission (prior to treatment) and 2 weeks after admission (after treatment). This protocol was implemented to ensure a consistent treatment duration across groups and to allow adequate time for artificial liver therapy in the relevant cohorts. Collected blood samples were allowed to clot at room temperature and were subsequently centrifuged at a low temperature (4°C, 3000 r/min, centrifuge radius 150 mm, for 15 minutes) within 5 hours. The serum was then collected and divided into aliquots; one portion was utilized for biochemical testing, while the other was stored at -80°C for future detection of HGF, OSM, and FGF-4, which are factors that regulate the transdifferentiation of MSCs. Throughout the treatment process, continuous monitoring of the electrocardiogram, blood pressure, and oxygen saturation was conducted, with particular attention paid to any changes in the patients' conditions. Laboratory Indicators Evaluation Before and after treatment, biochemical indicators such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), TB, and PTA were uniformly assessed for the three groups by the Department of Laboratory Medicine at the First Affiliated Hospital of Chongqing Medical University. The levels of HGF, OSM, and FGF-4 were quantified in the laboratory of the Department of Infectious Diseases at the same institution using the enzyme-linked immunosorbent assay. The assay kits were procured from Chongqing Van der Waals Biotechnology Co., Ltd., and all procedures were meticulously conducted in accordance with the manufacturer's instructions. Statistical methods Statistical analyses were performed using GraphPad Prism version 6.0 (GraphPad Software, USA). Measurement data were expressed as mean ± standard deviation (‾ x ± s ). Intergroup comparisons were conducted using one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test, while intragroup comparisons before and after treatment were analyzed using paired t-tests. Categorical variables were compared using the chi-square (χ²) test for multiple independent samples. The effect size (η²) was calculated to quantify the magnitude of treatment effects in one-way ANOVA, and 95% confidence intervals (CIs) for mean differences were reported to provide precision estimates for between-group comparisons. The Model for End-Stage Liver Disease (MELD) score was calculated using the following formula: MELD = 3.78 × ln [TB (mg/dL)] + 11.2 × ln (INR) + 9.57 × ln [Cr (mg/dL)] + 6.43. This randomized controlled trial was conducted and reported in accordance with the CONSORT (Consolidated Standards of Reporting Trials) guidelines. RESULTS Comparison of general characteristics among the three groups A total of 90 patients diagnosed with ACLF participated in the study. The groups were stratified into three categories: the control group (n = 30), the PE group (n = 30), and the DPMAS + PE group (n = 30). There were no statistically significant differences among these groups regarding gender, age, and disease duration distribution (P > 0.05). In the control group, there were 30 patients, comprising 18 males and 12 females, with a mean age of 50.1 ± 10.7 years. The PE group also included 30 patients, consisting of 15 males and 15 females, with a mean age of 52.1 ± 12.8 years, and a cumulative total of 54 sessions, averaging 1.8 sessions per individual. The DPMAS + PE group consisted of 30 patients, with 14 males and 16 females, who had a mean age of 51.6 ± 10.9 years and a total of 45 sessions, averaging 1.5 sessions per individual. Comparison of the pre-treatment conditions among the three groups There were no statistically significant differences in the mean age, biochemical indicators (ALT, AST, TB, and PTA), gender composition, or incidence of major complications (hepatic encephalopathy, bleeding, infection, and hepatorenal syndrome) among the three patient groups prior to treatment, as illustrated in Tables 1 and 2 . This finding indicates comparability among the groups. Table 1 Comparison of biochemical indexes among the three groups at admission Biochemical Index Control (n = 30) PE (n = 30) DPMAS + PE (n = 30) F P ALT (U/L) 330.92 ± 179.13 323.40 ± 194.31 343.96 ± 182.01 0.095 0.910 AST (U/L) 319.52 ± 171.09 327.36 ± 182.53 310.64 ± 180.78 0.066 0.936 TB (µmol/L) 314.12 ± 63.74 318.11 ± 126.40 332.51 ± 124.64 0.258 0.774 PTA (%) 33.76 ± 5.27 31.44 ± 6.24 32.44 ± 5.47 1.209 0.304 Abbreviations: PE, plasma exchange; DPMAS, dual plasma molecular adsorption system; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TB, total bilirubin; PTA, prothrombin activity. Table 2 Comparison of complication rate among the three groups at admission Complication Control (n = 30) PE (n = 30) DPMAS + PE (n = 30) χ2 P HE [Example (rate, %)] 6 (20.00) 5 (16.67) 4 (13.33) 0.480 0.787 Bleeding [Example (rate, %)] 0 (0) 0 (0) 0 (0) Infection [Example (rate, %)] 7 (23.33) 6 (20.00) 8 (26.67) 0.373 0.830 HRS [Example (rate, %)] 2 (6.67) 2 (6.67) 3 (10.00) 0.310 0.857 Abbreviations: PE, plasma exchange; DPMAS, dual plasma molecular adsorption system; HE, hepatic encephalopathy; HRS, hepatorenal syndrome. Comparison of liver function, coagulation before and after treatment among the three groups During the artificial liver treatment, patients generally tolerated the procedure well, with no significant adverse reactions noted. In all three groups, the majority of patients demonstrated marked improvement in their overall condition, gastrointestinal symptoms, and associated complications, with no fatalities reported. Comparisons conducted within each group before and after treatment revealed statistically significant improvements in various biochemical indicators (P < 0.0001). Between-group comparisons of the improvement rates of biochemical indicators indicated that both the PE group and the DPMAS + PE group exhibited significantly higher improvement rates for ALT, AST, TB, and PTA two weeks post-treatment compared to the control group (P < 0.05). With the exception of AST, the improvement rates of other biochemical indicators in the DPMAS + PE group were statistically different from those in the PE group (P < 0.05), as demonstrated in Table 3 . Table 3 Comparison of biochemical indexes among the three groups at admission and 2 weeks after treatment Biochemical Index Group (n = 30) Before treatment After treatment Improvement rate (%) Value (%) P η² ALT(U/L) Control 330.92 ± 179.13 156.32 ± 86.24 49.86 ± 12.92 < 0.001 0.245 PE 323.40 ± 194.31 113.92 ± 73.59 60.05 ± 17.67 a DPMAS + PE 343.96 ± 182.01 92.72 ± 35.59 69.11 ± 10.64 a, b AST(U/L) Control 319.52 ± 171.09 171.24 ± 95.71 43.74 ± 15.65 < 0.0001 0.237 PE 327.36 ± 182.53 117.04 ± 74.22 60.53 ± 17.38 a DPMAS + PE 310.64 ± 180.78 113.80 ± 81.05 61.90 ± 11.55 a TB(U/L) Control 314.12 ± 63.74 227.56 ± 84.11 28.28 ± 20.80 < 0.0001 0.393 PE 318.11 ± 126.40 180.44 ± 89.91 41.72 ± 19.94 a DPMAS + PE 332.51 ± 124.64 124.96 ± 75.94 63.34 ± 14.12 a, b PTA (%) Control 33.76 ± 5.27 41.24 ± 7.79 22.12 ± 13.94 < 0.0001 0.482 PE 31.44 ± 6.24 45.32 ± 11.54 43.71 ± 22.86 a DPMAS + PE 32.44 ± 5.47 53.24 ± 9.91 64.47 ± 16.70 a, b Abbreviations: PE, plasma exchange; DPMAS, dual plasma molecular adsorption system; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TB, total bilirubin; PTA, prothrombin activity; a compared with the control group, P <0.05, b compared with the PE group, P <0.05. The pairwise mean differences (95% confidence intervals, CI) in improvement rates were as follows: ALT—control vs PE, -10.19 (-18.84 to -1.54); control vs DPMAS + PE, -19.25 (-27.90 to -10.60); PE vs DPMAS + PE, -9.06 (-17.71 to -0.41); AST—control vs PE, -16.72 (-25.95 to -7.49); control vs DPMAS + PE, -18.09 (-27.32 to -8.86); PE vs DPMAS + PE, -1.37 (–10.60 to 7.86); TB—control vs PE, -11.03 (-21.60 to -0.47); control vs DPMAS + PE, -32.65 (-43.22 to -22.09); PE vs DPMAS + PE, -21.62 (-32.18 to -11.06); PTA—control vs PE, -20.73 (-31.72 to -9.75); control vs DPMAS + PE, -41.49 (-52.48 to -30.51); PE vs DPMAS + PE, -20.76 (-31.75 to -9.78). The visual representation in Fig. 1 A–D confirms these statistical findings, showing consistent patterns of improvement across ALT, AST, TB, and PTA. Comparison of MELD score before and after treatment among the three groups Consistent with the biochemical improvements, changes in the MELD score were further analyzed to evaluate overall liver functional recovery. Baseline MELD scores showed no statistically significant differences among the three groups ( P > 0.05), indicating comparable disease severity prior to treatment. After two weeks of therapy, significant reductions in MELD scores were observed in all three groups (P < 0.0001). Specifically, the mean ΔMELD differed significantly among the three groups (P < 0.0001). Between group comparisons confirmed that both the PE and DPMAS + PE groups achieved significantly greater MELD score improvements than the control group (P < 0.05), and the DPMAS + PE group showed a significantly larger reduction compared to the PE group (P < 0.05). The overall effect size was large (η² = 0.322), suggesting a substantial treatment effect on liver function severity. Detailed statistics are summarized in Table 4 . Table 4 Comparison of MELD score among the three groups at admission and 2 weeks after treatment Group Before treatment After treatment ΔMELD Value P η² Control 31.9 ± 2.8 26.7 ± 3.0 5.1 ± 2.5 <0.0001 0.322 PE 32.2 ± 3.7 24.7 ± 3.5 7.5 ± 3.3 a DPMAS + PE 32.3 ± 3.3 22.1 ± 3.6 10.2 ± 3.2 a, b Abbreviations: PE, plasma exchange; DPMAS, dual plasma molecular adsorption system; MELD, Model for End-Stage Liver Disease; a compared with the control group, P<0.05, b compared with the PE group, P<0.05. Comparison of HGF, OSM and FGF-4 levels before and after treatment among the three groups There were no statistically significant differences in the levels of serum HGF, OSM, and FGF-4 among the three groups prior to treatment (F = 0.121,0.413 and 0.073, P = 0.886,0.663 and 0.929), indicating comparability among the groups. Comparisons within each group before and after treatment demonstrated a significant increase in HGF levels, rising from (648.42 ± 325.33) ng/L to (907.93 ± 331.18) ng/L in the PE group and from (673.08 ± 326.09) ng/L to (1170.83 ± 444.32) ng/L in the DPMAS + PE group (t = 11.07 and 15.33, P < 0.0001). No significant differences were observed in the control group. Furthermore, no statistically significant differences in the levels of OSM and FGF-4 were found within any of the three groups before and after treatment. Pairwise comparisons among the three groups indicated that the HGF levels and their increments after two weeks of treatment were as follows: DPMAS + PE group > PE group > control group (two weeks post-treatment q = 3.648, 7.038, and 3.390, P < 0.05; two weeks post-treatment increment q = 8.892, 17.320, and 8.429, P < 0.0001). The pairwise mean differences (95% confidence intervals, CI) in HGF increments were as follows: control vs PE, − 225.80 (− 316.20 to − 135.50); control vs DPMAS + PE, − 464.10 (− 554.40 to − 373.70); and PE vs DPMAS + PE, − 238.20 (− 328.60 to − 147.90) ( P < 0.05). The overall effect size for HGF was large (η² = 0.633), indicating a substantial treatment effect. These findings are further illustrated in Fig. 2 A–B, which show both the intergroup differences and the temporal changes in serum HGF levels. Figure 2 A displays the greater post-treatment HGF elevations in the PE and DPMAS + PE groups, whereas Fig. 2 B highlights the upward trend after treatment. These visual results are consistent with the statistical analysis, and the detailed values are presented in Table 5 . However, no significant differences in the levels of OSM and FGF-4 were identified among the three groups post-treatment. Table 5 Comparison of regulatory factor of transdifferentiation among the three groups at admission and 2 weeks after treatment Biochemical Index Group (n = 30) Before treatment After treatment Increments Value P η² HGF (ng/L) Control 629.92 ± 370.43 663.58 ± 400.59 33.67 ± 128.44 <0.0001 0.633 PE 648.42 ± 325.33 907.93 ± 331.18 a 259.51 ± 128.45 a DPMAS + PE 673.08 ± 326.09 1170.83 ± 444.32 a, b 497.75 ± 177.82 a, b OSM (ng/L) Control 13.75 ± 6.94 14.50 ± 7.29 0.74 ± 3.64 ns 0.047 PE 15.39 ± 7.26 13.92 ± 6.98 -1.47 ± 4.79 DPMAS + PE 14.39 ± 6.92 14.17 ± 6.29 -0.23 ± 3.92 FGF-4 (ng/L) Control 122.73 ± 84.69 104.27 ± 61.86 -18.47 ± 78.51 ns 0.003 PE 124.30 ± 82.15 112.33 ± 75.92 -11.97 ± 103.77 DPMAS + PE 130.40 ± 78.72 121.37 ± 82.42 -9.03 ± 37.94 Abbreviations: PE, plasma exchange; DPMAS, dual plasma molecular adsorption system; HGF, hepatocyte growth factor; OSM, oncostatin M; FGF-4, fibroblast growth factor 4; a compared with the control group, P <0.05, b compared with the PE group, P <0.05. ns, no significant. DISCUSSION The artificial liver is a blood purification system that temporarily replaces certain liver functions, creating conditions conducive to liver recovery. PE is one of the earliest and most widely used methods in artificial liver systems. It is easy to operate and can quickly remove various toxins while replenishing plasma components, such as coagulation factors. While DPMAS is more effective than PE in removing bilirubin and inflammatory mediators, it does not provide coagulation factors. DPMAS + PE leverages the benefits of both treatments, effectively removing inflammatory factors and other toxins, while also replenishing coagulation factors and albumin[ 7 ]. In recent years, both domestic and international clinical studies have demonstrated the widespread application and remarkable therapeutic efficacy of artificial liver support systems in patients with liver failure[ 8 , 9 ]. Meanwhile, stem cell transplantation has emerged as a promising regenerative therapy, and its role in liver failure management continues to be actively explored[ 10 , 11 ]. Although these two therapeutic strategies share certain mechanistic relevance, studies investigating their sequential or combined use remain scarce and largely focus on biochemical improvement as the main outcome[ 12 , 13 ]. Regulatory factor of transdifferentiation, which govern the differentiation of progenitor or stem cells toward hepatocyte-like lineages, may better reflect the intrinsic regenerative potential of the hepatic microenvironment. Therefore, evaluating the dynamic changes in these factors became a central focus of this study. HGF primarily originates from non-parenchymal liver cells such as hepatic stellate cells, endothelial cells, and Kupffer cells. HGF activates downstream pathways by binding to its specific receptor c-Met, including the MAPK and PI3K-Akt pathways, among others, which influence hepatocyte regeneration[ 14 ]. Professor Li found that HGF plays a crucial role in the differentiation of human bone marrow mesenchymal stem cells into hepatocytes[ 15 ]. Domestic studies have also shown that adipose tissue-derived MSCs, influenced by HGF, differentiate into hepatocytes and demonstrate therapeutic effects on liver damage in mice by reducing serum ALT, AST activity, and TB levels[ 16 ]. In our study, we found that the HGF levels in two groups of patients significantly increased after receiving two weeks of artificial liver treatment. Although liver damage can compensatorily increase the synthesis and secretion of HGF, and exogenous plasma can supplement a certain level of HGF, the duration of this study far exceeded the half-life of exogenous HGF. Additionally, there was no significant difference in HGF levels before and after treatment in the control group. Therefore, we believe that the increase in HGF levels is primarily due to the improvement of the hepatic microenvironment by the artificial liver. Compared to the PE group, the DPMAS + PE group both replenish key components for maintaining homeostasis—albumin and coagulation factors. Additionally, the dual-filter adsorption system of the former can remove a broader spectrum of medium and large molecules, thereby enhancing the breadth and depth of treatment[ 17 ]. Our research indicates that compared to PE, DPMAS + PE demonstrates a more significant ability to elevate HGF levels. This could be attributed to the broader clearance of inflammatory factors, which reduces oxidative stress and provides a more favorable environment for hepatocyte regeneration. It is also possible that certain cytokines inhibit HGF levels in pathways related to hepatocyte regeneration, and the deeper clearance effect of DPMAS + PE mitigates this impact. Further basic research is needed to explore and substantiate these findings. Additionally, the fewer number of treatments per patient in this study suggests that a single treatment can maintain high levels of HGF for an extended period. Domestic studies have demonstrated that plasma exchange combined with mesenchymal stem cells is safe for treating ACLF; however, it has not significantly improved short-term prognosis[ 12 ]. In our study, this combined therapy significantly increased HGF levels, providing a theoretical basis for the use of artificial liver treatment combined with stem cell transplantation. OSM is a member of the IL-6 family. Upon binding to its co-receptor gp130, it activates multiple signaling pathways, including JAK/STAT, MAPK, and PI3K/AKT, which are involved in stem cell differentiation and liver regeneration, among other physiological functions[ 18 ]. Fibroblast growth factors are a family of cell signaling proteins that mediate various biological processes, including cell proliferation, metabolism, differentiation, tissue repair, and regeneration, by interacting with tyrosine kinase receptors. FGF-4 is a member of this subfamily and functions through paracrine signaling[ 19 ]. Professor Zhang's team found that MSCs induced by HGF and FGF-4 differentiate to express liver cell-specific markers such as ALB, AFP, and CK-18 and have the ability to store glycogen[ 20 ]. Azadeh Raoufil et al. also obtained similar results using mesenchymal stem cells extracted from the umbilical vein that were induced by HGF and OSM[ 21 ]. In our study, the levels of OSM and FGF-4 in the control group, PE group, and DPMAS + PE group did not show significant changes before and after treatment, nor were there any significant differences between the groups post-treatment. Many domestic and international scholars have found that OSM or FGF-4 is often induced together with HGF in cases where MSCs successfully differentiate into liver cells[ 22 ]. This may be because these two cytokines do not play a dominant or critical role in the hepatocyte regeneration pathway. Therefore, artificial liver treatment may not promote hepatocyte regeneration by merely increasing the levels of OSM and FGF-4; however, this requires further clinical data and basic research to confirm. Nevertheless, our results indicate that artificial liver treatment increased the level of HGF without causing a significant decrease in the levels of OSM and FGF-4. This may facilitate the mechanism of MSCs transdifferentiation in the repair and regeneration of hepatocytes in cases of acute-on-chronic liver failure. Our study also focused on several biomarkers that can predict treatment outcomes and risks for patients, including ALT, AST, TB, and PTA. The use of DPMAS + PE resulted in significantly greater improvements in ALT, TB, and PTA compared to the PE group alone. Furthermore, both groups treated with artificial liver therapy demonstrated better outcomes than the control group. This aligns with recent clinical trial findings that DPMAS + PE is more effective for treating ACLF compared to single PE treatment, indicating that DPMAS + PE is superior to PE in enhancing the hepatic microenvironment[ 23 ]. To comprehensively evaluate the improvement in hepatic function, we compared MELD scores before and after treatment and found significant reductions in both artificial liver groups. Chen et al. reported that plasma exchange effectively improves MELD scores and short-term outcomes[ 24 ]. Our study further confirmed this finding, with the greatest decrease in MELD scores observed in the DPMAS + PE group, suggesting that this combined approach may better promote the recovery of hepatic synthetic and detoxification functions. The present study has certain limitations. First, since most cases of liver failure in China are caused by chronic hepatitis B virus (HBV) infection, all patients enrolled in this study had HBV-related acute-on-chronic liver failure. Therefore, the generalizability of our findings to liver failure of other etiologies—such as alcoholic, non-alcoholic fatty liver disease (NAFLD), or drug-induced injury—remains uncertain and warrants further multicenter clinical verification Second, we only measured a limited panel of regulatory factor of transdifferentiation; thus, the laboratory data alone cannot provide direct evidence of MSCs transdifferentiation. Moreover, the endpoint of our study was set at two weeks, which is insufficient to reflect long-term survival outcomes and sustained hepatocyte regeneration. However, the purpose of this study was to establish a theoretical foundation for subsequent sequential stem-cell transplantation. For this reason, a two-week observation period was deliberately chosen to capture short-term biochemical and regenerative responses, in alignment with the practical time window for sequential therapy. In recent years, while the understanding of artificial liver therapy primarily focuses on removing inflammatory mediators and metabolites, our research has found that HGF levels significantly increase after artificial liver treatment[ 8 ]. This suggests that artificial liver therapy may also aid in the regeneration and recovery of liver cells by promoting the transformation of MSCs into hepatocytes. Compared to PE, DPMAS + PE shows a more significant increase in HGF levels, indicating that DPMAS + PE not only removes inflammatory mediators and metabolites more thoroughly but may also have better therapeutic effects on promoting hepatocyte differentiation. However, fundamental research on this therapeutic mechanism remains insufficient, which somewhat limits the technological innovation and clinical application of artificial liver techniques. Therefore, actively exploring and elucidating the role and mechanisms of artificial livers in improving the liver microenvironment and promoting hepatocyte regeneration is an important direction for further research. CONCLUSION In conclusion, patients with ACLF who received artificial liver therapy showed a significant increase in HGF levels, with the DPMAS + PE group experiencing a notably higher increase compared to the PE group. The study demonstrated that, two weeks post-treatment, HGF levels and their increments were ranked as follows: DPMAS + PE group > PE group > control group (two weeks post-treatment q = 3.648, 7.038, and 3.390, P < 0.05; two weeks post-treatment increment q = 8.892, 17.320, and 8.429, P < 0.0001). These findings suggest that enhancing HGF levels to promote the differentiation of mesenchymal stem cells into hepatocytes could be a promising addition to the mechanisms underlying artificial liver therapy for ACLF. However, before further validating this therapeutic approach, additional clinical samples are necessary for careful and thorough evaluation. Furthermore, the current lack of foundational research has limited innovations and improvements in artificial liver technology. Moving forward, more in-depth basic research combined with larger clinical trials will be essential to advancing this therapy. Declarations Acknowledgements: This work was supported by the Special Fund of Beijing iGandan Foundation [iGandanF-1082022-RGG041 to F.Y.], Scientific and Technological Research Program of Chongqing Municipal Education Commission [KJQN202100401 to F.Y.], and Program for Youth Innovation in Future Medicine, Chongqing Medical University [W0101 to F.Y.]. Competing interests: The authors declare that they have no competing interests. Ethics approval and consent to participate: This study was conducted in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University (Approval No. 20226701). Written informed consent was obtained from all participants prior to enrollment. Consent for publication: Not applicable. Data availability: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Authors contributions: Y. conceived the study and designed the experiments. S.H.Y. performed the main experiments and analyzed the data, and X.H.Y. provided serum samples and performed some of the experiments. F.Y. and B.Q. draft and revised the manuscript. All authors read and approved the final manuscript. References Gu WY, Xu BY, Zheng X, Chen J, Wang XB, Huang Y, Gao YH, Meng ZJ, Qian ZP, Liu F, Lu XB, Shang J, Li H, Wang SY, Sun X, Li H. Acute-on-Chronic Liver Failure in China: Rationale for Developing a Patient Registry and Baseline Characteristics. Am J Epidemiol. 2018;187(9):1829–39. 10.1093/aje/kwy083] . [PMID: 29762630. Cheng X, Zhan Y, Liu Y, Zeng X, Wang Z, Wang F, Mao Y, Na S. A clinical study of non-bioartificial liver DPMAES support system in hepatitis B-related acute-on-chronic liver failure. Scientific reports 2024; 14(1): 1772 [PMID: 38245594 10.1038/s41598-024-52206-0] Xiao Ling K, Peng L, Jian Feng Z, Wei C, Wei Yan Y, Nan S, Cheng Qi G, Zhi Wei W. Stromal Derived Factor-1/CXCR4 Axis Involved in Bone Marrow Mesenchymal Stem Cells Recruitment to Injured Liver. Stem Cells Int 2016; 2016: 8906945 [PMID: 26880995 10.1155/2016/8906945] Yuan M, Hu X, Yao L, Jiang Y, Li L. Mesenchymal stem cell homing to improve therapeutic efficacy in liver disease. Stem Cell Res Ther. 2022;13(1):179. 10.1186/s13287-022-02858-4] . [PMID: 35505419. Banas A, Teratani T, Yamamoto Y, Tokuhara M, Takeshita F, Quinn G, Okochi H, Ochiya T. Adipose tissue-derived mesenchymal stem cells as a source of human hepatocytes. Hepatology. 2007;46(1):219–28. 10.1002/hep.21704] . [PMID: 17596885. Campard D, Lysy PA, Najimi M, Sokal EM. Native umbilical cord matrix stem cells express hepatic markers and differentiate into hepatocyte-like cells. Gastroenterology. 2008;134(3):833–48. 10.1053/j.gastro.2007.12.024] . [PMID: 18243183. Chen Y, Han T, Duan Z. Clinical application of artificial liver and blood purification: expert consensus recommendations. Hepatol Int. 2023;17(1):4–17. 10.1007/s12072-022-10430-8] . [PMID: 36324040. Maiwall R, Bajpai M, Singh A, Agarwal T, Kumar G, Bharadwaj A, Nautiyal N, Tevethia H, Jagdish RK, Vijayaraghavan R, Choudhury A, Mathur RP, Hidam A, Pati NT, Sharma MK, Kumar A, Sarin SK. Standard-Volume Plasma Exchange Improves Outcomes in Patients With Acute Liver Failure: A Randomized Controlled Trial. Clin Gastroenterol Hepatol. 2022;20(4):e831–54. 10.1016/j.cgh.2021.01.036] . [PMID: 33524593. Ma Y, Xu Y, Du L, Bai L, Tang H. Association between volume of processed plasma and total bilirubin reduction during plasma adsorption for severe liver disease. Eur J Med Res. 2025;30(1):175. 10.1186/s40001-025-02419-4] . [PMID: 40089798. Jia Y, Shu X, Yang X, Sun H, Cao H, Cao H, Zhang K, Xu Q, Li G, Yang Y. Enhanced therapeutic effects of umbilical cord mesenchymal stem cells after prolonged treatment for HBV-related liver failure and liver cirrhosis. Stem Cell Res Ther. 2020;11(1):277. 10.1186/s13287-020-01787-4] . [PMID: 32650827. Zhang K, Sun H, Cao H, Jia Y, Shu X, Cao H, Zhang Y, Yang X. The impact of recipient age on the effects of umbilical cord mesenchymal stem cells on HBV-related acute-on-chronic liver failure and liver cirrhosis. Stem Cell Res Ther. 2021;12(1):466. 10.1186/s13287-021-02544-x] . [PMID: 34416908. Xu WX, He HL, Pan SW, Chen YL, Zhang ML, Zhu S, Gao ZL, Peng L, Li JG. Combination Treatments of Plasma Exchange and Umbilical Cord-Derived Mesenchymal Stem Cell Transplantation for Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure: A Clinical Trial in China. Stem Cells Int 2019; 2019: 4130757 [PMID: 30863450 10.1155/2019/4130757] Li YH, Xu Y, Wu HM, Yang J, Yang LH, Yue-Meng W. Umbilical Cord-Derived Mesenchymal Stem Cell Transplantation in Hepatitis B Virus Related Acute-on-Chronic Liver Failure Treated with Plasma Exchange and Entecavir: a 24-Month Prospective Study. Stem Cell Rev Rep. 2016;12(6):645–53. 10.1007/s12015-016-9683-3] . [PMID: 27687792 DOI:. Trusolino L, Bertotti A, Comoglio PM. MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol. 2010;11(12):834–48. 10.1038/nrm3012] . [PMID: 21102609. Li F, Liu Y, Cai Y, Li X, Bai M, Sun T, Du L. Ultrasound Irradiation Combined with Hepatocyte Growth Factor Accelerate the Hepatic Differentiation of Human Bone Marrow Mesenchymal Stem Cells. Ultrasound Med Biol. 2018;44(5):1044–52. 10.1016/j.ultrasmedbio.2018.01.005] . [PMID: 29499919. Yin L, Zhu Y, Yang J, Ni Y, Zhou Z, Chen Y, Wen L. Adipose tissue-derived mesenchymal stem cells differentiated into hepatocyte-like cells in vivo and in vitro. Mol Med Rep. 2015;11(3):1722–32. 10.3892/mmr.2014.2935] . [PMID: 25395242. Wang L, Xu W, Zhu S, Lin G, Lai J, Zhang Y, Liu Y, Zheng L, Luo Q, Gao Z, Xie C, Peng L. Double Plasma Molecular Adsorption System with Sequential Low-dose Plasma Exchange in Patients with Hepatitis B Virus-related Acute-on-chronic Liver Failure: A Prospective Study. J Clin Transl Hepatol. 2023;11(4):908–17. 10.14218/jcth.2022.00254] . [PMID: 37408804. Wolf CL, Pruett C, Lighter D, Jorcyk CL. The clinical relevance of OSM in inflammatory diseases: a comprehensive review. Front Immunol. 2023;14:1239732. 10.3389/fimmu.2023.1239732] . [PMID: 37841259. Farooq M, Khan AW, Kim MS, Choi S. The Role of Fibroblast Growth Factor (FGF) Signaling in Tissue Repair and Regeneration. Cells 2021; 10(11) [PMID: 34831463 DOI: 10.3390/cells10113242]. Zhang YN, Lie PC, Wei X. Differentiation of mesenchymal stromal cells derived from umbilical cord Wharton's jelly into hepatocyte-like cells. Cytotherapy. 2009;11(5):548–58. [PMID: 19657806 DOI: 10.1080/14653240903051533]. Raoufil A, Aminil A, Azadbakht M, Farhadifar F, Rahram Nikhn Frrfin Fthi NF. Production of hepatocyte-like cells from human umbilical vein mesenchymal stem cells. Ital J Anat Embryol. 2015;120(3):150–61. [PMID: 27086414]. Afshari A, Shamdani S, Uzan G, Naserian S, Azarpira N. Different approaches for transformation of mesenchymal stem cells into hepatocyte-like cells. Stem Cell Res Ther 2020; 11(1): 54 [PMID: 32033595 10.1186/s13287-020-1555-8] Xiang Y, Li R, Cai J, Jiang Q. Three Artificial Liver Models of Treatment of Acute-on-Chronic Liver Failure. Ther Clin Risk Manag. 2024;20:731–40. [PMID: 39479527 DOI: 10.2147/tcrm.S485620]. Chen YY, Li H, Xu BY, Zheng X, Li BL, Wang XB, Huang Y, Gao YH, Qian ZP, Liu F, Lu XB, Shang J, Li H, Wang SY, Zhang YH, Meng ZJ. Plasma Exchange-Based Non-bioartificial Liver Support System Improves the Short-Term Outcomes of Patients With Hepatitis B Virus-Associated Acute-on-Chronic Liver Failure: A Multicenter Prospective Cohort Study. Front Med. 2021;8:779744. 10.3389/fmed.2021.779744] . [PMID: 34869500. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 14 Apr, 2026 Reviewers agreed at journal 14 Apr, 2026 Reviewers invited by journal 01 Apr, 2026 Editor assigned by journal 17 Feb, 2026 Editor invited by journal 14 Feb, 2026 Submission checks completed at journal 13 Feb, 2026 First submitted to journal 13 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8843627","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":616536108,"identity":"12317fcc-e1b8-4cac-a737-76e5fc8e27f5","order_by":0,"name":"Shuhan Yang","email":"","orcid":"","institution":"Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shuhan","middleName":"","lastName":"Yang","suffix":""},{"id":616536111,"identity":"4581d43f-4fed-4a4e-99d0-95f6bce6b07c","order_by":1,"name":"Xuhong Yang","email":"","orcid":"","institution":"Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xuhong","middleName":"","lastName":"Yang","suffix":""},{"id":616536113,"identity":"79b8d21a-52e3-4dd0-b6b1-08ab6cb8c8f3","order_by":2,"name":"Bo Qin","email":"","orcid":"","institution":"Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Bo","middleName":"","lastName":"Qin","suffix":""},{"id":616536114,"identity":"0fd8d0af-9fd2-4f3c-bf70-b2739c199f4e","order_by":3,"name":"Fan Yang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1klEQVRIiWNgGAWjYBACPiD+wGDDIMPGwMD4gMGACC0glTMY0hh4gAxmA9K0gNgSRDmMjb35YcOHBBsePonkY5U/Cu7IM7AfProBrxaeY4aNMxLSeNgk0tJu8xg8M2zgSUu7gVeLRIL5Y94fh3nYeM6Y3WYwOMzYIMFjhl+L/POPzTwJIC3nvxX+MDhsT1iLBI8hRAt7DxsDj8HhRMJaeHIKIX5hbzOWBmpJbiPkF3724xtBISYn38z88OOPP4dt+9kPH8OrBYu9pCkfBaNgFIyCUYANAABid0JjkpiREgAAAABJRU5ErkJggg==","orcid":"","institution":"Chongqing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Fan","middleName":"","lastName":"Yang","suffix":""}],"badges":[],"createdAt":"2026-02-10 17:09:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8843627/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8843627/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106347943,"identity":"397cea34-5d9e-4d3b-a122-e9d71894a3cd","added_by":"auto","created_at":"2026-04-07 16:43:22","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":105639,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImprovement rates in liver biochemical index after treatment among the three groups.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A) \u003c/strong\u003eALT improvement rate (%). \u003cstrong\u003e(B) \u003c/strong\u003eAST improvement rate (%). \u003cstrong\u003e(C)\u003c/strong\u003e TB improvement rate (%). \u003cstrong\u003e(D)\u003c/strong\u003e PTA improvement rate (%). Values are shown as mean ± SD (n=30),\u003csup\u003e *\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05,\u003csup\u003e ***\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001,\u003csup\u003e ****\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.0001, One-way ANOVA followed by the Tukey tests. \u003cstrong\u003eAbbreviations:\u003c/strong\u003e ALT, \u003cem\u003ealanine aminotransferase\u003c/em\u003e; AST,\u003cem\u003e aspartate aminotransferase\u003c/em\u003e; TB, total bilirubin A; PTA, prothrombin activity; PE, plasma exchange; DPMAS, dual plasma molecular adsorption system; ns, no significant.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8843627/v1/642b940e7626b1ab990c6ce6.jpg"},{"id":106347944,"identity":"853c0ada-c533-45da-9042-f512cd4213dd","added_by":"auto","created_at":"2026-04-07 16:43:22","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":50716,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A) \u003c/strong\u003eHGF increment (ng/L) after treatment in the control, PE, and DPMAS+PE groups. \u003cstrong\u003e(B) \u003c/strong\u003eSerum HGF levels before and after treatment, showing the temporal trend within each group. Values are shown as mean ± SD (n=30),\u003csup\u003e *\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05,\u003csup\u003e ****\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.0001, One-way ANOVA followed by the Tukey tests. \u003cstrong\u003eAbbreviations:\u003c/strong\u003e HGF, \u003cem\u003ehepatocyte growth factor\u003c/em\u003e; PE, plasma exchange; DPMAS, dual plasma molecular adsorption system.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8843627/v1/6e64fefd39a202e01f5b199b.jpg"},{"id":106404728,"identity":"0882033b-514b-48cc-85ff-aefb19d680d0","added_by":"auto","created_at":"2026-04-08 09:16:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1082271,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8843627/v1/51b2a53f-6093-4393-b5f9-acb1c2f2491b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of Artificial Liver on the Levels of Regulatory Factors of Transdifferentiation in Acute-on-Chronic Liver Failure","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eAcute-on-chronic liver failure (ACLF) is a severe condition characterized by the sudden deterioration of liver function in patients with underlying chronic liver disease. In China, the primary cause of ACLF is hepatitis B virus infection[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. One important treatment for liver failure is the use of artificial liver therapy. In recent years, the artificial liver has experienced ongoing innovations based on plasma exchange (PE), particularly through the integration of the dual plasma molecular adsorption system (DPMAS), which has been extensively validated in clinical practice. Current research in artificial liver therapy primarily focuses on the dynamic changes of inflammatory mediators and metabolites within the liver microenvironment[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, there is limited literature on the role of mesenchymal stem cells (MSCs) in hepatocyte regeneration. Studies suggest that MSCs can migrate to damaged areas and transdifferentiate into hepatocytes[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This process depends on the support of the liver microenvironment, with regulatory factor of transdifferentiation such as hepatocyte growth factor (HGF), oncostatin M (OSM), and fibroblast growth factor 4 (FGF-4) playing crucial roles in MSCs' transdifferentiation into hepatocytes[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. This study aims to explore the potential and mechanisms of MSCs' transdifferentiation during liver cell regeneration by assessing the levels of these regulatory factors before and after artificial liver treatment.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eGeneral information\u003c/h2\u003e \u003cp\u003e This study followed the Chinese Clinical Practice Guidelines and received approval from the Ethical Committee of the First Affiliated Hospital of Chongqing Medical University (approval number:20226701). All patients provided written informed consent before treatment and agreed to participate in the study. This randomized controlled trial included 90 patients admitted to the internal medicine department of the First Affiliated Hospital of Chongqing Medical University from October 2022 to October 2023. Patients were evaluated based on age, gender, classification, biochemical indicators, and complications, and were randomly divided into three groups according to the principle of \"minimum imbalance index allocation\": the control group (n\u0026thinsp;=\u0026thinsp;30), the PE group (n\u0026thinsp;=\u0026thinsp;30), and the DPMAS\u0026thinsp;+\u0026thinsp;PE group (n\u0026thinsp;=\u0026thinsp;30).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRandomization and Blinding\u003c/h3\u003e\n\u003cp\u003eParticipants were randomly assigned to the control, PE, or DPMAS\u0026thinsp;+\u0026thinsp;PE groups using a computer-assisted minimization method based on the minimum imbalance index allocation principle to ensure balanced baseline characteristics among groups. The allocation sequence was generated by an independent statistician prior to patient enrollment. To maintain allocation concealment, group assignments were implemented by a research coordinator who was not involved in patient recruitment or outcome assessment. Due to the nature of the artificial liver interventions, blinding of participants and treating clinicians was not feasible. However, laboratory personnel and data analysts were blinded to treatment allocation.\u003c/p\u003e\n\u003ch3\u003eDiagnostic,inclusion,and exclusion criteria\u003c/h3\u003e\n\u003cp\u003e The inclusion criteria for this study are derived from the \"Guidelines for the Diagnosis and Treatment of Liver Failure,\" established by the Infectious Diseases and Hepatology Branch of the Chinese Medical Association in 2018. These guidelines classify liver failure into four stages: pre-stage, early-stage, mid-stage, and late-stage. Acute-on-chronic liver failure (ACLF) is defined as a syndrome presenting with jaundice and coagulation disorders, accompanied by complications such as hepatic encephalopathy, ascites, infections, and hepatorenal syndrome, all precipitated by various factors within the context of chronic liver disease. Jaundice manifests rapidly and progresses, with serum total bilirubin (TB) levels reaching ten times or more above the upper limit of normal (ULN) or increasing by 17.1 \u0026micro;mol/L or more per day. Additionally, signs of bleeding are evident, with prothrombin activity (PTA)\u0026thinsp;\u0026le;\u0026thinsp;40% (or an international normalized ratio [INR]\u0026thinsp;\u0026ge;\u0026thinsp;1.5). The inclusion criteria for this study specifically target patients with early to mid-stage ACLF attributable to hepatitis B. In contrast, the exclusion criteria encompass individuals aged\u0026thinsp;\u0026lt;\u0026thinsp;18 years or \u0026gt;\u0026thinsp;70 years, late-stage pregnancy, late-stage acute-on-chronic liver failure (i.e., PTA\u0026thinsp;\u0026le;\u0026thinsp;20% or INR\u0026thinsp;\u0026ge;\u0026thinsp;2.6, or the presence of two or more complications or extrahepatic organ failure), concurrent infections with other viral hepatitis strains (such as HCV, HIV, \u003cem\u003eetc\u003c/em\u003e.), liver failure resulting from alternative etiologies (such as alcoholic liver disease autoimmune liver disease, \u003cem\u003eetc\u003c/em\u003e.), and other relative contraindications as delineated in the 2022 \"Expert Consensus on the Clinical Application of Artificial Liver Blood Purification Technology\" (including active bleeding or disseminated intravascular coagulation, hemodynamic instability, unstable periods of cardiovascular or cerebral infarction, and severe allergies to plasma, heparin, protamine, \u003cem\u003eetc\u003c/em\u003e.).\u003c/p\u003e\n\u003ch3\u003eResearch methods\u003c/h3\u003e\n\u003cp\u003eAll patients received comprehensive internal medicine treatment, which included antioxidants, hepatocyte membrane protectants, anti-inflammatory agents for the liver, medications to alleviate intrahepatic cholestasis, drugs to enhance hepatic microcirculation, and supportive treatments such as plasma and albumin. Complications were also prevented and managed effectively, with all patients diagnosed with hepatitis B receiving nucleoside analogs antiviral therapy. The PE group utilized a novel membrane selective plasma separator, Evacure-4A (Kawasaki, Japan), which operated at a blood flow rate of 90\u0026ndash;120 ml/min, with 2000 ml of fresh plasma exchanged during each session. The DPMAS\u0026thinsp;+\u0026thinsp;PE group underwent DPMAS followed by PE. For DPMAS, a sequential application of an anion exchange resin adsorber BS330 (Zhuhai Jianfan) and a neutral resin hemoperfusion column HA330-Ⅱ (Zhuhai Jianfan) was employed. The initial treatment for both the PE and DPMAS\u0026thinsp;+\u0026thinsp;PE groups was completed within 3 days of admission (no later than 1 week), with no more than two treatments administered per week post-admission. Blood samples from the three groups were collected at two time points: upon admission (prior to treatment) and 2 weeks after admission (after treatment). This protocol was implemented to ensure a consistent treatment duration across groups and to allow adequate time for artificial liver therapy in the relevant cohorts. Collected blood samples were allowed to clot at room temperature and were subsequently centrifuged at a low temperature (4\u0026deg;C, 3000 r/min, centrifuge radius 150 mm, for 15 minutes) within 5 hours. The serum was then collected and divided into aliquots; one portion was utilized for biochemical testing, while the other was stored at -80\u0026deg;C for future detection of HGF, OSM, and FGF-4, which are factors that regulate the transdifferentiation of MSCs. Throughout the treatment process, continuous monitoring of the electrocardiogram, blood pressure, and oxygen saturation was conducted, with particular attention paid to any changes in the patients' conditions.\u003c/p\u003e\n\u003ch3\u003eLaboratory Indicators Evaluation\u003c/h3\u003e\n\u003cp\u003eBefore and after treatment, biochemical indicators such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), TB, and PTA were uniformly assessed for the three groups by the Department of Laboratory Medicine at the First Affiliated Hospital of Chongqing Medical University. The levels of HGF, OSM, and FGF-4 were quantified in the laboratory of the Department of Infectious Diseases at the same institution using the enzyme-linked immunosorbent assay. The assay kits were procured from Chongqing Van der Waals Biotechnology Co., Ltd., and all procedures were meticulously conducted in accordance with the manufacturer's instructions.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical methods\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using GraphPad Prism version 6.0 (GraphPad Software, USA). Measurement data were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (\u0026oline;\u003cem\u003ex\u0026thinsp;\u0026plusmn;\u0026thinsp;s\u003c/em\u003e). Intergroup comparisons were conducted using one-way analysis of variance (ANOVA) followed by Tukey\u0026rsquo;s post hoc test, while intragroup comparisons before and after treatment were analyzed using paired t-tests. Categorical variables were compared using the chi-square (χ\u0026sup2;) test for multiple independent samples.\u003c/p\u003e \u003cp\u003eThe effect size (η\u0026sup2;) was calculated to quantify the magnitude of treatment effects in one-way ANOVA, and 95% confidence intervals (CIs) for mean differences were reported to provide precision estimates for between-group comparisons. The Model for End-Stage Liver Disease (MELD) score was calculated using the following formula: MELD\u0026thinsp;=\u0026thinsp;3.78 \u0026times; ln [TB (mg/dL)]\u0026thinsp;+\u0026thinsp;11.2 \u0026times; ln (INR)\u0026thinsp;+\u0026thinsp;9.57 \u0026times; ln [Cr (mg/dL)]\u0026thinsp;+\u0026thinsp;6.43.\u003c/p\u003e \u003cp\u003e This randomized controlled trial was conducted and reported in accordance with the CONSORT (Consolidated Standards of Reporting Trials) guidelines.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eComparison of general characteristics among the three groups\u003c/h2\u003e \u003cp\u003eA total of 90 patients diagnosed with ACLF participated in the study. The groups were stratified into three categories: the control group (n\u0026thinsp;=\u0026thinsp;30), the PE group (n\u0026thinsp;=\u0026thinsp;30), and the DPMAS\u0026thinsp;+\u0026thinsp;PE group (n\u0026thinsp;=\u0026thinsp;30). There were no statistically significant differences among these groups regarding gender, age, and disease duration distribution (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). In the control group, there were 30 patients, comprising 18 males and 12 females, with a mean age of 50.1\u0026thinsp;\u0026plusmn;\u0026thinsp;10.7 years. The PE group also included 30 patients, consisting of 15 males and 15 females, with a mean age of 52.1\u0026thinsp;\u0026plusmn;\u0026thinsp;12.8 years, and a cumulative total of 54 sessions, averaging 1.8 sessions per individual. The DPMAS\u0026thinsp;+\u0026thinsp;PE group consisted of 30 patients, with 14 males and 16 females, who had a mean age of 51.6\u0026thinsp;\u0026plusmn;\u0026thinsp;10.9 years and a total of 45 sessions, averaging 1.5 sessions per individual.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eComparison of the pre-treatment conditions among the three groups\u003c/h2\u003e \u003cp\u003eThere were no statistically significant differences in the mean age, biochemical indicators (ALT, AST, TB, and PTA), gender composition, or incidence of major complications (hepatic encephalopathy, bleeding, infection, and hepatorenal syndrome) among the three patient groups prior to treatment, as illustrated in Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. This finding indicates comparability among the groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of biochemical indexes among the three groups at admission\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBiochemical Index\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePE\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDPMAS\u0026thinsp;+\u0026thinsp;PE\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eF\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e330.92\u0026thinsp;\u0026plusmn;\u0026thinsp;179.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e323.40\u0026thinsp;\u0026plusmn;\u0026thinsp;194.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e343.96\u0026thinsp;\u0026plusmn;\u0026thinsp;182.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.095\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.910\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e319.52\u0026thinsp;\u0026plusmn;\u0026thinsp;171.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e327.36\u0026thinsp;\u0026plusmn;\u0026thinsp;182.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e310.64\u0026thinsp;\u0026plusmn;\u0026thinsp;180.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.066\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.936\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTB (\u0026micro;mol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e314.12\u0026thinsp;\u0026plusmn;\u0026thinsp;63.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e318.11\u0026thinsp;\u0026plusmn;\u0026thinsp;126.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e332.51\u0026thinsp;\u0026plusmn;\u0026thinsp;124.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.258\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.774\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePTA (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e33.76\u0026thinsp;\u0026plusmn;\u0026thinsp;5.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e31.44\u0026thinsp;\u0026plusmn;\u0026thinsp;6.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e32.44\u0026thinsp;\u0026plusmn;\u0026thinsp;5.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.209\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.304\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eAbbreviations: PE, plasma exchange; DPMAS, dual plasma molecular adsorption system; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TB, total bilirubin; PTA, prothrombin activity.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of complication rate among the three groups at admission\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplication\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePE\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDPMAS\u0026thinsp;+\u0026thinsp;PE\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eχ2\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHE [Example (rate, %)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (20.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (16.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (13.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.480\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.787\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBleeding [Example (rate, %)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfection [Example (rate, %)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (23.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (20.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (26.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.373\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.830\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHRS [Example (rate, %)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (6.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (6.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (10.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.310\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.857\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eAbbreviations: PE, plasma exchange; DPMAS, dual plasma molecular adsorption system; HE, hepatic encephalopathy; HRS, hepatorenal syndrome.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eComparison of liver function, coagulation before and after treatment among the three groups\u003c/h2\u003e \u003cp\u003eDuring the artificial liver treatment, patients generally tolerated the procedure well, with no significant adverse reactions noted. In all three groups, the majority of patients demonstrated marked improvement in their overall condition, gastrointestinal symptoms, and associated complications, with no fatalities reported. Comparisons conducted within each group before and after treatment revealed statistically significant improvements in various biochemical indicators (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e \u003cp\u003eBetween-group comparisons of the improvement rates of biochemical indicators indicated that both the PE group and the DPMAS\u0026thinsp;+\u0026thinsp;PE group exhibited significantly higher improvement rates for ALT, AST, TB, and PTA two weeks post-treatment compared to the control group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). With the exception of AST, the improvement rates of other biochemical indicators in the DPMAS\u0026thinsp;+\u0026thinsp;PE group were statistically different from those in the PE group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), as demonstrated in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of biochemical indexes among the three groups at admission and 2 weeks after treatment\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBiochemical Index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBefore treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAfter treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eImprovement rate (%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eValue (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eη\u0026sup2;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT(U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e330.92\u0026thinsp;\u0026plusmn;\u0026thinsp;179.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e156.32\u0026thinsp;\u0026plusmn;\u0026thinsp;86.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e49.86\u0026thinsp;\u0026plusmn;\u0026thinsp;12.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.245\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e323.40\u0026thinsp;\u0026plusmn;\u0026thinsp;194.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e113.92\u0026thinsp;\u0026plusmn;\u0026thinsp;73.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e60.05\u0026thinsp;\u0026plusmn;\u0026thinsp;17.67 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDPMAS\u0026thinsp;+\u0026thinsp;PE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e343.96\u0026thinsp;\u0026plusmn;\u0026thinsp;182.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e92.72\u0026thinsp;\u0026plusmn;\u0026thinsp;35.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e69.11\u0026thinsp;\u0026plusmn;\u0026thinsp;10.64 \u003csup\u003ea, b\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST(U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e319.52\u0026thinsp;\u0026plusmn;\u0026thinsp;171.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e171.24\u0026thinsp;\u0026plusmn;\u0026thinsp;95.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e43.74\u0026thinsp;\u0026plusmn;\u0026thinsp;15.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.237\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e327.36\u0026thinsp;\u0026plusmn;\u0026thinsp;182.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e117.04\u0026thinsp;\u0026plusmn;\u0026thinsp;74.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e60.53\u0026thinsp;\u0026plusmn;\u0026thinsp;17.38 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDPMAS\u0026thinsp;+\u0026thinsp;PE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e310.64\u0026thinsp;\u0026plusmn;\u0026thinsp;180.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e113.80\u0026thinsp;\u0026plusmn;\u0026thinsp;81.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e61.90\u0026thinsp;\u0026plusmn;\u0026thinsp;11.55 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTB(U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e314.12\u0026thinsp;\u0026plusmn;\u0026thinsp;63.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e227.56\u0026thinsp;\u0026plusmn;\u0026thinsp;84.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28.28\u0026thinsp;\u0026plusmn;\u0026thinsp;20.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.393\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e318.11\u0026thinsp;\u0026plusmn;\u0026thinsp;126.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e180.44\u0026thinsp;\u0026plusmn;\u0026thinsp;89.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e41.72\u0026thinsp;\u0026plusmn;\u0026thinsp;19.94 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDPMAS\u0026thinsp;+\u0026thinsp;PE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e332.51\u0026thinsp;\u0026plusmn;\u0026thinsp;124.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e124.96\u0026thinsp;\u0026plusmn;\u0026thinsp;75.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e63.34\u0026thinsp;\u0026plusmn;\u0026thinsp;14.12 \u003csup\u003ea, b\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePTA (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33.76\u0026thinsp;\u0026plusmn;\u0026thinsp;5.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41.24\u0026thinsp;\u0026plusmn;\u0026thinsp;7.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22.12\u0026thinsp;\u0026plusmn;\u0026thinsp;13.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.482\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.44\u0026thinsp;\u0026plusmn;\u0026thinsp;6.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45.32\u0026thinsp;\u0026plusmn;\u0026thinsp;11.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e43.71\u0026thinsp;\u0026plusmn;\u0026thinsp;22.86 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDPMAS\u0026thinsp;+\u0026thinsp;PE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32.44\u0026thinsp;\u0026plusmn;\u0026thinsp;5.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e53.24\u0026thinsp;\u0026plusmn;\u0026thinsp;9.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e64.47\u0026thinsp;\u0026plusmn;\u0026thinsp;16.70 \u003csup\u003ea, b\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eAbbreviations: PE, plasma exchange; DPMAS, dual plasma molecular adsorption system; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TB, total bilirubin; PTA, prothrombin activity; \u003csup\u003ea\u003c/sup\u003e compared with the control group, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05, \u003csup\u003eb\u003c/sup\u003e compared with the PE group, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe pairwise mean differences (95% confidence intervals, CI) in improvement rates were as follows: ALT\u0026mdash;control vs PE, -10.19 (-18.84 to -1.54); control vs DPMAS\u0026thinsp;+\u0026thinsp;PE, -19.25 (-27.90 to -10.60); PE vs DPMAS\u0026thinsp;+\u0026thinsp;PE, -9.06 (-17.71 to -0.41); AST\u0026mdash;control vs PE, -16.72 (-25.95 to -7.49); control vs DPMAS\u0026thinsp;+\u0026thinsp;PE, -18.09 (-27.32 to -8.86); PE vs DPMAS\u0026thinsp;+\u0026thinsp;PE, -1.37 (\u0026ndash;10.60 to 7.86); TB\u0026mdash;control vs PE, -11.03 (-21.60 to -0.47); control vs DPMAS\u0026thinsp;+\u0026thinsp;PE, -32.65 (-43.22 to -22.09); PE vs DPMAS\u0026thinsp;+\u0026thinsp;PE, -21.62 (-32.18 to -11.06); PTA\u0026mdash;control vs PE, -20.73 (-31.72 to -9.75); control vs DPMAS\u0026thinsp;+\u0026thinsp;PE, -41.49 (-52.48 to -30.51); PE vs DPMAS\u0026thinsp;+\u0026thinsp;PE, -20.76 (-31.75 to -9.78).\u003c/p\u003e \u003cp\u003eThe visual representation in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA\u0026ndash;D confirms these statistical findings, showing consistent patterns of improvement across ALT, AST, TB, and PTA.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eComparison of MELD score before and after treatment among the three groups\u003c/h2\u003e \u003cp\u003eConsistent with the biochemical improvements, changes in the MELD score were further analyzed to evaluate overall liver functional recovery.\u003c/p\u003e \u003cp\u003eBaseline MELD scores showed no statistically significant differences among the three groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05), indicating comparable disease severity prior to treatment. After two weeks of therapy, significant reductions in MELD scores were observed in all three groups (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e \u003cp\u003eSpecifically, the mean ΔMELD differed significantly among the three groups (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Between group comparisons confirmed that both the PE and DPMAS\u0026thinsp;+\u0026thinsp;PE groups achieved significantly greater MELD score improvements than the control group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and the DPMAS\u0026thinsp;+\u0026thinsp;PE group showed a significantly larger reduction compared to the PE group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eThe overall effect size was large (η\u0026sup2; = 0.322), suggesting a substantial treatment effect on liver function severity. Detailed statistics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of MELD score among the three groups at admission and 2 weeks after treatment\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBefore treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAfter treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003eΔMELD\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eValue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eη\u0026sup2;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.322\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDPMAS\u0026thinsp;+\u0026thinsp;PE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2 \u003csup\u003ea, b\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eAbbreviations: PE, plasma exchange; DPMAS, dual plasma molecular adsorption system; MELD, Model for End-Stage Liver Disease; a compared with the control group, P\u0026lt;0.05, b compared with the PE group, P\u0026lt;0.05.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eComparison of HGF, OSM and FGF-4 levels before and after treatment among the three groups\u003c/h2\u003e \u003cp\u003eThere were no statistically significant differences in the levels of serum HGF, OSM, and FGF-4 among the three groups prior to treatment (F\u0026thinsp;=\u0026thinsp;0.121,0.413 and 0.073, P\u0026thinsp;=\u0026thinsp;0.886,0.663 and 0.929), indicating comparability among the groups. Comparisons within each group before and after treatment demonstrated a significant increase in HGF levels, rising from (648.42\u0026thinsp;\u0026plusmn;\u0026thinsp;325.33) ng/L to (907.93\u0026thinsp;\u0026plusmn;\u0026thinsp;331.18) ng/L in the PE group and from (673.08\u0026thinsp;\u0026plusmn;\u0026thinsp;326.09) ng/L to (1170.83\u0026thinsp;\u0026plusmn;\u0026thinsp;444.32) ng/L in the DPMAS\u0026thinsp;+\u0026thinsp;PE group (t\u0026thinsp;=\u0026thinsp;11.07 and 15.33, P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). No significant differences were observed in the control group. Furthermore, no statistically significant differences in the levels of OSM and FGF-4 were found within any of the three groups before and after treatment. Pairwise comparisons among the three groups indicated that the HGF levels and their increments after two weeks of treatment were as follows: DPMAS\u0026thinsp;+\u0026thinsp;PE group\u0026thinsp;\u0026gt;\u0026thinsp;PE group\u0026thinsp;\u0026gt;\u0026thinsp;control group (two weeks post-treatment q\u0026thinsp;=\u0026thinsp;3.648, 7.038, and 3.390, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05; two weeks post-treatment increment q\u0026thinsp;=\u0026thinsp;8.892, 17.320, and 8.429, P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e \u003cp\u003eThe pairwise mean differences (95% confidence intervals, CI) in HGF increments were as follows: control vs PE, \u0026minus;\u0026thinsp;225.80 (\u0026minus;\u0026thinsp;316.20 to \u0026minus;\u0026thinsp;135.50); control vs DPMAS\u0026thinsp;+\u0026thinsp;PE, \u0026minus;\u0026thinsp;464.10 (\u0026minus;\u0026thinsp;554.40 to \u0026minus;\u0026thinsp;373.70); and PE vs DPMAS\u0026thinsp;+\u0026thinsp;PE, \u0026minus;\u0026thinsp;238.20 (\u0026minus;\u0026thinsp;328.60 to \u0026minus;\u0026thinsp;147.90) (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The overall effect size for HGF was large (η\u0026sup2; = 0.633), indicating a substantial treatment effect.\u003c/p\u003e \u003cp\u003eThese findings are further illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA\u0026ndash;B, which show both the intergroup differences and the temporal changes in serum HGF levels. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA displays the greater post-treatment HGF elevations in the PE and DPMAS\u0026thinsp;+\u0026thinsp;PE groups, whereas Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB highlights the upward trend after treatment. These visual results are consistent with the statistical analysis, and the detailed values are presented in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. However, no significant differences in the levels of OSM and FGF-4 were identified among the three groups post-treatment.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of regulatory factor of transdifferentiation among the three groups at admission and 2 weeks after treatment\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" morerows=\"1\" nameend=\"c2\" namest=\"c1\" rowspan=\"2\"\u003e \u003cp\u003eBiochemical Index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBefore treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAfter treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003eIncrements\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eValue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eη\u0026sup2;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eHGF (ng/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e629.92\u0026thinsp;\u0026plusmn;\u0026thinsp;370.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e663.58\u0026thinsp;\u0026plusmn;\u0026thinsp;400.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e33.67\u0026thinsp;\u0026plusmn;\u0026thinsp;128.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"6\" rowspan=\"6\"\u003e \u003cp\u003e0.633\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e648.42\u0026thinsp;\u0026plusmn;\u0026thinsp;325.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e907.93\u0026thinsp;\u0026plusmn;\u0026thinsp;331.18 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e259.51\u0026thinsp;\u0026plusmn;\u0026thinsp;128.45 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDPMAS\u0026thinsp;+\u0026thinsp;PE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e673.08\u0026thinsp;\u0026plusmn;\u0026thinsp;326.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1170.83\u0026thinsp;\u0026plusmn;\u0026thinsp;444.32 \u003csup\u003ea, b\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e497.75\u0026thinsp;\u0026plusmn;\u0026thinsp;177.82 \u003csup\u003ea, b\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOSM (ng/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.75\u0026thinsp;\u0026plusmn;\u0026thinsp;6.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14.50\u0026thinsp;\u0026plusmn;\u0026thinsp;7.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.74\u0026thinsp;\u0026plusmn;\u0026thinsp;3.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ens\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15.39\u0026thinsp;\u0026plusmn;\u0026thinsp;7.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.92\u0026thinsp;\u0026plusmn;\u0026thinsp;6.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-1.47\u0026thinsp;\u0026plusmn;\u0026thinsp;4.79\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDPMAS\u0026thinsp;+\u0026thinsp;PE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14.39\u0026thinsp;\u0026plusmn;\u0026thinsp;6.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14.17\u0026thinsp;\u0026plusmn;\u0026thinsp;6.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.23\u0026thinsp;\u0026plusmn;\u0026thinsp;3.92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eFGF-4 (ng/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e122.73\u0026thinsp;\u0026plusmn;\u0026thinsp;84.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e104.27\u0026thinsp;\u0026plusmn;\u0026thinsp;61.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-18.47\u0026thinsp;\u0026plusmn;\u0026thinsp;78.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003ens\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e124.30\u0026thinsp;\u0026plusmn;\u0026thinsp;82.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e112.33\u0026thinsp;\u0026plusmn;\u0026thinsp;75.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-11.97\u0026thinsp;\u0026plusmn;\u0026thinsp;103.77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDPMAS\u0026thinsp;+\u0026thinsp;PE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e130.40\u0026thinsp;\u0026plusmn;\u0026thinsp;78.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e121.37\u0026thinsp;\u0026plusmn;\u0026thinsp;82.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-9.03\u0026thinsp;\u0026plusmn;\u0026thinsp;37.94\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eAbbreviations: PE, plasma exchange; DPMAS, dual plasma molecular adsorption system; HGF, hepatocyte growth factor; OSM, oncostatin M; FGF-4, fibroblast growth factor 4; \u003csup\u003ea\u003c/sup\u003e compared with the control group, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05, \u003csup\u003eb\u003c/sup\u003e compared with the PE group, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05. ns, no significant.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe artificial liver is a blood purification system that temporarily replaces certain liver functions, creating conditions conducive to liver recovery. PE is one of the earliest and most widely used methods in artificial liver systems. It is easy to operate and can quickly remove various toxins while replenishing plasma components, such as coagulation factors. While DPMAS is more effective than PE in removing bilirubin and inflammatory mediators, it does not provide coagulation factors. DPMAS\u0026thinsp;+\u0026thinsp;PE leverages the benefits of both treatments, effectively removing inflammatory factors and other toxins, while also replenishing coagulation factors and albumin[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn recent years, both domestic and international clinical studies have demonstrated the widespread application and remarkable therapeutic efficacy of artificial liver support systems in patients with liver failure[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Meanwhile, stem cell transplantation has emerged as a promising regenerative therapy, and its role in liver failure management continues to be actively explored[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Although these two therapeutic strategies share certain mechanistic relevance, studies investigating their sequential or combined use remain scarce and largely focus on biochemical improvement as the main outcome[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Regulatory factor of transdifferentiation, which govern the differentiation of progenitor or stem cells toward hepatocyte-like lineages, may better reflect the intrinsic regenerative potential of the hepatic microenvironment. Therefore, evaluating the dynamic changes in these factors became a central focus of this study.\u003c/p\u003e \u003cp\u003eHGF primarily originates from non-parenchymal liver cells such as hepatic stellate cells, endothelial cells, and Kupffer cells. HGF activates downstream pathways by binding to its specific receptor c-Met, including the MAPK and PI3K-Akt pathways, among others, which influence hepatocyte regeneration[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Professor Li found that HGF plays a crucial role in the differentiation of human bone marrow mesenchymal stem cells into hepatocytes[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Domestic studies have also shown that adipose tissue-derived MSCs, influenced by HGF, differentiate into hepatocytes and demonstrate therapeutic effects on liver damage in mice by reducing serum ALT, AST activity, and TB levels[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In our study, we found that the HGF levels in two groups of patients significantly increased after receiving two weeks of artificial liver treatment. Although liver damage can compensatorily increase the synthesis and secretion of HGF, and exogenous plasma can supplement a certain level of HGF, the duration of this study far exceeded the half-life of exogenous HGF. Additionally, there was no significant difference in HGF levels before and after treatment in the control group. Therefore, we believe that the increase in HGF levels is primarily due to the improvement of the hepatic microenvironment by the artificial liver. Compared to the PE group, the DPMAS\u0026thinsp;+\u0026thinsp;PE group both replenish key components for maintaining homeostasis\u0026mdash;albumin and coagulation factors. Additionally, the dual-filter adsorption system of the former can remove a broader spectrum of medium and large molecules, thereby enhancing the breadth and depth of treatment[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Our research indicates that compared to PE, DPMAS\u0026thinsp;+\u0026thinsp;PE demonstrates a more significant ability to elevate HGF levels. This could be attributed to the broader clearance of inflammatory factors, which reduces oxidative stress and provides a more favorable environment for hepatocyte regeneration. It is also possible that certain cytokines inhibit HGF levels in pathways related to hepatocyte regeneration, and the deeper clearance effect of DPMAS\u0026thinsp;+\u0026thinsp;PE mitigates this impact. Further basic research is needed to explore and substantiate these findings. Additionally, the fewer number of treatments per patient in this study suggests that a single treatment can maintain high levels of HGF for an extended period. Domestic studies have demonstrated that plasma exchange combined with mesenchymal stem cells is safe for treating ACLF; however, it has not significantly improved short-term prognosis[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In our study, this combined therapy significantly increased HGF levels, providing a theoretical basis for the use of artificial liver treatment combined with stem cell transplantation.\u003c/p\u003e \u003cp\u003eOSM is a member of the IL-6 family. Upon binding to its co-receptor gp130, it activates multiple signaling pathways, including JAK/STAT, MAPK, and PI3K/AKT, which are involved in stem cell differentiation and liver regeneration, among other physiological functions[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Fibroblast growth factors are a family of cell signaling proteins that mediate various biological processes, including cell proliferation, metabolism, differentiation, tissue repair, and regeneration, by interacting with tyrosine kinase receptors. FGF-4 is a member of this subfamily and functions through paracrine signaling[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Professor Zhang's team found that MSCs induced by HGF and FGF-4 differentiate to express liver cell-specific markers such as ALB, AFP, and CK-18 and have the ability to store glycogen[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Azadeh Raoufil et al. also obtained similar results using mesenchymal stem cells extracted from the umbilical vein that were induced by HGF and OSM[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In our study, the levels of OSM and FGF-4 in the control group, PE group, and DPMAS\u0026thinsp;+\u0026thinsp;PE group did not show significant changes before and after treatment, nor were there any significant differences between the groups post-treatment. Many domestic and international scholars have found that OSM or FGF-4 is often induced together with HGF in cases where MSCs successfully differentiate into liver cells[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. This may be because these two cytokines do not play a dominant or critical role in the hepatocyte regeneration pathway. Therefore, artificial liver treatment may not promote hepatocyte regeneration by merely increasing the levels of OSM and FGF-4; however, this requires further clinical data and basic research to confirm. Nevertheless, our results indicate that artificial liver treatment increased the level of HGF without causing a significant decrease in the levels of OSM and FGF-4. This may facilitate the mechanism of MSCs transdifferentiation in the repair and regeneration of hepatocytes in cases of acute-on-chronic liver failure.\u003c/p\u003e \u003cp\u003eOur study also focused on several biomarkers that can predict treatment outcomes and risks for patients, including ALT, AST, TB, and PTA. The use of DPMAS\u0026thinsp;+\u0026thinsp;PE resulted in significantly greater improvements in ALT, TB, and PTA compared to the PE group alone. Furthermore, both groups treated with artificial liver therapy demonstrated better outcomes than the control group. This aligns with recent clinical trial findings that DPMAS\u0026thinsp;+\u0026thinsp;PE is more effective for treating ACLF compared to single PE treatment, indicating that DPMAS\u0026thinsp;+\u0026thinsp;PE is superior to PE in enhancing the hepatic microenvironment[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. To comprehensively evaluate the improvement in hepatic function, we compared MELD scores before and after treatment and found significant reductions in both artificial liver groups. Chen et al. reported that plasma exchange effectively improves MELD scores and short-term outcomes[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Our study further confirmed this finding, with the greatest decrease in MELD scores observed in the DPMAS\u0026thinsp;+\u0026thinsp;PE group, suggesting that this combined approach may better promote the recovery of hepatic synthetic and detoxification functions.\u003c/p\u003e \u003cp\u003eThe present study has certain limitations. First, since most cases of liver failure in China are caused by chronic hepatitis B virus (HBV) infection, all patients enrolled in this study had HBV-related acute-on-chronic liver failure. Therefore, the generalizability of our findings to liver failure of other etiologies\u0026mdash;such as alcoholic, non-alcoholic fatty liver disease (NAFLD), or drug-induced injury\u0026mdash;remains uncertain and warrants further multicenter clinical verification Second, we only measured a limited panel of regulatory factor of transdifferentiation; thus, the laboratory data alone cannot provide direct evidence of MSCs transdifferentiation. Moreover, the endpoint of our study was set at two weeks, which is insufficient to reflect long-term survival outcomes and sustained hepatocyte regeneration. However, the purpose of this study was to establish a theoretical foundation for subsequent sequential stem-cell transplantation. For this reason, a two-week observation period was deliberately chosen to capture short-term biochemical and regenerative responses, in alignment with the practical time window for sequential therapy.\u003c/p\u003e \u003cp\u003eIn recent years, while the understanding of artificial liver therapy primarily focuses on removing inflammatory mediators and metabolites, our research has found that HGF levels significantly increase after artificial liver treatment[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. This suggests that artificial liver therapy may also aid in the regeneration and recovery of liver cells by promoting the transformation of MSCs into hepatocytes. Compared to PE, DPMAS\u0026thinsp;+\u0026thinsp;PE shows a more significant increase in HGF levels, indicating that DPMAS\u0026thinsp;+\u0026thinsp;PE not only removes inflammatory mediators and metabolites more thoroughly but may also have better therapeutic effects on promoting hepatocyte differentiation. However, fundamental research on this therapeutic mechanism remains insufficient, which somewhat limits the technological innovation and clinical application of artificial liver techniques. Therefore, actively exploring and elucidating the role and mechanisms of artificial livers in improving the liver microenvironment and promoting hepatocyte regeneration is an important direction for further research.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn conclusion, patients with ACLF who received artificial liver therapy showed a significant increase in HGF levels, with the DPMAS\u0026thinsp;+\u0026thinsp;PE group experiencing a notably higher increase compared to the PE group. The study demonstrated that, two weeks post-treatment, HGF levels and their increments were ranked as follows: DPMAS\u0026thinsp;+\u0026thinsp;PE group\u0026thinsp;\u0026gt;\u0026thinsp;PE group\u0026thinsp;\u0026gt;\u0026thinsp;control group (two weeks post-treatment q\u0026thinsp;=\u0026thinsp;3.648, 7.038, and 3.390, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05; two weeks post-treatment increment q\u0026thinsp;=\u0026thinsp;8.892, 17.320, and 8.429, P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). These findings suggest that enhancing HGF levels to promote the differentiation of mesenchymal stem cells into hepatocytes could be a promising addition to the mechanisms underlying artificial liver therapy for ACLF. However, before further validating this therapeutic approach, additional clinical samples are necessary for careful and thorough evaluation. Furthermore, the current lack of foundational research has limited innovations and improvements in artificial liver technology. Moving forward, more in-depth basic research combined with larger clinical trials will be essential to advancing this therapy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003col\u003e\n\u003cli\u003e\u003cstrong\u003eAcknowledgements: \u003c/strong\u003eThis work was supported by the Special Fund of Beijing iGandan Foundation [iGandanF-1082022-RGG041 to F.Y.], Scientific and Technological Research Program of Chongqing Municipal Education Commission [KJQN202100401 to F.Y.], and Program for Youth Innovation in Future Medicine, Chongqing Medical University [W0101 to F.Y.].\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare that they have no competing interests.\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e This study was conducted in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University (Approval No. 20226701). Written informed consent was obtained from all participants prior to enrollment.\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eConsent\u003c/strong\u003e \u003cstrong\u003efor publication: \u003c/strong\u003eNot applicable.\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eAuthors contributions: \u003c/strong\u003eY. conceived the study and designed the experiments. S.H.Y. performed the main experiments and analyzed the data, and X.H.Y. provided serum samples and performed some of the experiments. F.Y. and B.Q. draft and revised the manuscript. 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[PMID: 34869500.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Artificial liver, Acute-on-chronic liver failure, Plasma exchange, Dual plasma molecular adsorption system, Mesenchymal stem cells, Regulatory factor of transdifferentiation","lastPublishedDoi":"10.21203/rs.3.rs-8843627/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8843627/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBACKGROUND\u003c/h2\u003e \u003cp\u003eAcute-on-chronic liver failure (ACLF) is a severe liver disease. Artificial liver based on plasma exchange (PE) has undergone continuous innovation, particularly through the integration of the dual plasma molecular adsorption system (DPMAS), which has been widely validated clinically. Current research on artificial liver primarily focuses on the dynamic changes in inflammatory mediators and metabolites. However, there is limited study on the mechanism of mesenchymal stem cells differentiating into liver cells, specifically the level of transdifferentiation regulatory factors.\u003c/p\u003e\u003ch2\u003eAIM\u003c/h2\u003e \u003cp\u003eTo investigate the potential and differences during liver cell regeneration in patients with ACLF receiving different modes of artificial liver.\u003c/p\u003e\u003ch2\u003eMETHODS\u003c/h2\u003e \u003cp\u003e90 patients with ACLF were divided into three groups: the control group (n\u0026thinsp;=\u0026thinsp;30), the PE group (n\u0026thinsp;=\u0026thinsp;30), and the DPMAS\u0026thinsp;+\u0026thinsp;PE group (n\u0026thinsp;=\u0026thinsp;30). We compared changes in the levels of three regulatory factors of transdifferentiation\u0026mdash;hepatocyte growth factor (HGF), oncostatin M (OSM), and fibroblast growth factor-4 (FGF-4)\u0026mdash;before and after treatment in the three groups.\u003c/p\u003e\u003ch2\u003eRESULTS\u003c/h2\u003e \u003cp\u003eCompared to before treatment, both the PE group and the DPMAS\u0026thinsp;+\u0026thinsp;PE group showed a significant increase in HGF levels (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), while the control group exhibited no significant change. Pairwise comparisons among the three groups indicated that the levels and increases in HGF followed this order: DPMAS\u0026thinsp;+\u0026thinsp;PE group\u0026thinsp;\u0026gt;\u0026thinsp;PE group\u0026thinsp;\u0026gt;\u0026thinsp;control group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eCONCLUSION\u003c/h2\u003e \u003cp\u003eArtificial liver therapy can aid in regenerating and recovering liver cells by increasing HGF levels. DPMAS\u0026thinsp;+\u0026thinsp;PE demonstrates better performance in this regard compared to PE alone.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003eChinese Clinical Trial Registry, ChiCTR2500098113, retrospectively registered on 3 March 2025.\u003c/p\u003e","manuscriptTitle":"Impact of Artificial Liver on the Levels of Regulatory Factors of Transdifferentiation in Acute-on-Chronic Liver Failure","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-07 16:43:18","doi":"10.21203/rs.3.rs-8843627/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-04-14T16:52:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"72463981632865650704258842973738300078","date":"2026-04-14T14:59:09+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-01T23:31:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-18T03:27:52+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-14T06:43:55+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-13T17:51:37+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Gastroenterology","date":"2026-02-13T17:46:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f1688c3d-a1b3-4498-9b99-9650d1d540e9","owner":[],"postedDate":"April 7th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-07T16:43:18+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-07 16:43:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8843627","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8843627","identity":"rs-8843627","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}