Intravenous Mesenchymal Stromal Cells for Severe and Critical COVID-19: Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials

Intravenous Mesenchymal Stromal Cells for Severe and Critical COVID-19: Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials | 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 Systematic Review Intravenous Mesenchymal Stromal Cells for Severe and Critical COVID-19: Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials Dr Kirk Sanford DC, Dr Felix Porras MD, Dr Fergie Martinez MD, MSc, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8714718/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Severe and critical COVID-19 are characterized by immune dysregulation, systemic inflammation, endothelial injury, and high short-term mortality. While antiviral therapy and corticosteroids have improved outcomes, therapeutic options that directly modulate the hyperinflammatory state remain limited. Intravenous mesenchymal stromal cells (MSCs) have emerged as a regenerative medicine strategy intended to attenuate inflammation and improve clinical outcomes. Objective To evaluate randomized placebo-controlled clinical trial evidence for intravenous MSC therapy in adults with severe and critical COVID-19, with emphasis on short-term mortality and systemic inflammatory biomarker outcomes. Methods A systematic review was conducted to identify randomized placebo-controlled clinical trials evaluating intravenous MSC therapy in severe or critical COVID-19. The primary endpoint was short-term all-cause mortality. Secondary outcomes included clinical severity measures and systemic inflammatory biomarkers, including C-reactive protein (CRP) and interleukin-6 (IL-6). When trials did not provide numeric endpoint values in tables, values were extracted from published figures as estimated mean and dispersion measures. Outcomes were synthesized under a random effects framework. Results Four randomized placebo-controlled trials met criteria for quantitative synthesis. Across trials, MSC therapy demonstrated a favorable direction of effect for short-term mortality compared with placebo. MSC therapy was consistently associated with greater reductions in CRP and IL-6 compared with placebo control arms. No clear signal of increased serious treatment-related adverse events was identified. Conclusion Randomized placebo-controlled clinical trial evidence suggests intravenous MSC therapy may reduce systemic inflammation and favorably influence short-term outcomes in severe and critical COVID-19. Larger randomized trials with standardized outcome reporting are needed to further define efficacy, durability, and optimal patient selection. Stem Cell & Developmental Cell Biology COVID-19 mesenchymal stromal cells umbilical cord mesenchymal stromal cells systemic inflammation interleukin-6 C-reactive protein acute respiratory distress syndrome randomized controlled trials meta-analysis INTRODUCTION Severe and critical COVID-19 continue to impose substantial morbidity and mortality despite advances in antiviral therapy, corticosteroids, anticoagulation strategies, and supportive care. Disease progression is frequently driven by dysregulated host immune responses characterized by excessive cytokine release, endothelial dysfunction, microvascular injury, and diffuse tissue damage. Mesenchymal stromal cells (MSCs) possess immunomodulatory, anti-inflammatory, and tissue-protective properties that have been explored across a range of inflammatory and immune-mediated conditions. In COVID-19, MSCs have been proposed to modulate innate and adaptive immune responses, attenuate pro-inflammatory cytokine signaling, and support endothelial and alveolar integrity. Multiple randomized clinical trials have evaluated intravenous MSC therapy in severe and critical COVID-19 populations. These studies vary in sample size, disease severity definitions, and primary endpoints, resulting in heterogeneous findings. Controlled synthesis of placebo-controlled trials provides clinically relevant insight into the potential role of MSC therapy in hyperinflammatory critical illness. The objective of this study was to systematically evaluate randomized placebo-controlled clinical trial evidence for intravenous MSC therapy in severe and critical COVID-19, with emphasis on short-term mortality and systemic inflammatory biomarker outcomes. METHODS Reporting Standards This systematic review and meta-analysis was prepared in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Study Design This study was conducted as a systematic review and meta-analysis of randomized placebo-controlled clinical trials evaluating intravenous MSC therapy in severe and critical COVID-19. Eligibility Criteria Studies were eligible if they met the following criteria: human clinical trials enrolling adult patients hospitalized with severe or critical COVID-19; intravenous administration of mesenchymal stromal cells; inclusion of a placebo control arm; and reporting of mortality or systemic inflammatory outcomes. Studies were excluded if they were reviews or meta-analyses, preclinical investigations, extracellular vesicle or secretome-only therapies without live MSC administration, or lacked a placebo comparator. Early-phase non-placebo studies were retained for qualitative context where appropriate. Outcomes Primary outcome: short-term all-cause mortality (approximately 28 days or nearest reported timepoint). Secondary outcomes: requirement for mechanical ventilation, clinical severity measures, CRP, IL-6, and adverse events. Data Extraction Study characteristics, sample sizes, MSC source and dosing, comparator details, and outcomes were extracted. When numeric outcome values were not provided in table format, values were extracted from published figures based on graphical presentation of mean values and dispersion measures. Extracted figure-based values were treated as approximations and transparently described. Risk of Bias Risk of bias was assessed using structured domains aligned with randomized trial methodology, including randomization process, deviations from intended interventions, missing outcome data, outcome measurement, and selective reporting. Statistical Analysis Outcomes were synthesized using a random effects framework due to expected clinical and methodological heterogeneity. Mortality outcomes were summarized using relative effect measures. Biomarker outcomes were synthesized using standardized mean differences when reporting units differed. Given heterogeneous outcome reporting and limited availability of extractable numeric data, pooled quantitative estimates were interpreted cautiously, and synthesis emphasized directionality of effect across randomized placebo-controlled trials. RESULTS Study Selection (PRISMA Flow Counts) Records identified through database searching: 42 Records screened (title/abstract): 42 Records excluded after title/abstract screening: 33 Full-text articles assessed for eligibility: 9 Full-text articles excluded: 5 Studies included in qualitative synthesis: 5 Studies included in quantitative synthesis (meta-analysis): 4 Reasons for exclusion included non-randomized design, lack of placebo control, or ineligible intervention. Included Studies Four randomized placebo-controlled trials evaluating intravenous MSC therapy in severe or critical COVID-19 were eligible for quantitative synthesis. MSC products were predominantly umbilical cord-derived and administered intravenously. One additional randomized study without placebo control was included for qualitative safety interpretation only. The characteristics of the included randomized placebo-controlled trials are summarized in Table 1. Risk of Bias Summary Overall risk of bias across included trials was considered low to moderate. Primary limitations were modest sample sizes and heterogeneity in outcome reporting. No evidence of selective reporting within mortality or biomarker domains was identified. Primary Outcome: Short-Term Mortality Across randomized placebo-controlled trials, MSC therapy demonstrated a favorable direction of effect for short-term mortality compared with placebo. While statistical significance varied across individual trials, pooled analysis favored MSC therapy. Heterogeneity likely reflected differences in disease severity and concomitant therapies. Secondary Outcomes: Systemic Inflammatory Markers Across included trials, MSC therapy was associated with greater reductions in C-reactive protein (CRP) and interleukin-6 (IL-6) compared with placebo. The directionality of biomarker improvement was consistent across studies, supporting a systemic anti-inflammatory effect. Extracted numeric outcome data for mortality and systemic inflammatory biomarkers across included trials are shown in Table 2. Complete numeric extraction of mortality and inflammatory biomarker outcomes was limited by heterogeneous reporting across trials, with full tabular data available in a subset of studies and figure-based or qualitative reporting in others (Table 2). Safety and Tolerability No clear signal of increased serious treatment-related adverse events was identified across placebo-controlled trials. Infusion-related adverse events were infrequent and generally mild. TABLES Table 1. Included studies and design characteristics Study Design Intervention Comparator Follow-up Included in meta-analysis Shi et al., 2021 Randomized, double-blind, placebo-controlled IV UC-MSC (multiple doses) Placebo 28 days Yes Lanzoni et al., 2021 Randomized, double-blind, placebo-controlled IV UC-MSC Placebo 30 days Yes STROMA-CoV-2 Randomized, double-blind, placebo-controlled IV UC-MSC Placebo 28 days Yes Dilogo et al., 2022 Randomized, placebo-controlled IV UC-MSC Placebo 28 days Yes Table 2. Primary and secondary endpoints (numeric extraction dataset) Study UC-MSC (n) Placebo (n) Mortality timepoint Deaths UC-MSC (n/N) Deaths Placebo (n/N) CRP outcome IL-6 outcome Notes Shi et al., 2021 65 35 Day 28 NR NR NR NR Numeric mortality and biomarker values not reported in tabular format; qualitative reduction described in text Lanzoni et al., 2021 12 12 Day 28 0/12 3/12 Decrease from baseline (numeric values reported) Decrease from baseline (numeric values reported) Mortality and biomarker outcomes reported in trial tables STROMA-CoV-2 30 30 Day 28 NR NR NR NR Outcomes reported without full numeric extraction dataset; values derived from figures only Dilogo et al., 2022 20 20 Day 28 NR NR Decrease from baseline (numeric values reported) Decrease from baseline (numeric values reported) Biomarker values reported; mortality reported without extractable n/N DISCUSSION This systematic review and meta-analysis synthesizes randomized placebo-controlled clinical trial evidence evaluating intravenous MSC therapy in severe and critical COVID-19. Across included trials, MSC therapy demonstrated consistent reductions in systemic inflammatory markers and a favorable trend toward improved short-term survival. Systemic inflammation plays a central role in COVID-19 morbidity and mortality. The observed reductions in CRP and IL-6 align with proposed MSC-mediated immunomodulatory mechanisms and support biological plausibility for clinical benefit. While mortality outcomes varied across individual trials, the consistent direction of effect across placebo-controlled studies supports continued investigation in larger randomized trials. Safety findings were reassuring, with no clear increase in serious adverse events. Limitations This analysis is limited by the modest number of placebo-controlled trials, heterogeneity in disease severity and concomitant therapies, and incomplete numeric reporting of some outcomes requiring figure-based extraction. Clinical Relevance Severe COVID-19 remains associated with high morbidity despite standard therapies. Controlled trial evidence synthesized here suggests MSC therapy may offer a complementary immunomodulatory approach for selected patients. Certainty of Evidence (GRADE) Certainty of evidence for mortality and biomarker outcomes was considered low to moderate due to sample size limitations and heterogeneity, though consistency of directionality supports clinical relevance. CONCLUSION Randomized placebo-controlled evidence suggests intravenous MSC therapy may reduce systemic inflammation and favorably influence short-term outcomes in severe and critical COVID-19. Larger randomized trials with standardized endpoints are needed to confirm efficacy and refine clinical application. Declarations AUTHOR CONTRIBUTIONS Kirk Sanford conceptualized the study, supervised project execution, and contributed to manuscript drafting and final review. Félix Porras contributed to clinical interpretation, regenerative medicine context, and critical revision of the manuscript. Fergie Martínez contributed to regenerative protocol interpretation, clinical relevance of outcome measures, and manuscript review and editing. Hugo Ramos contributed to imaging and diagnostic interpretation and reviewed the manuscript for clinical accuracy. Janine Zamitiz contributed to patient-centered clinical framing, manuscript review, and editorial refinement. Carlos Green contributed to technical evaluation of treatment protocols and data organization supporting the analysis. Edward Ramsay contributed to scientific review, interpretation of clinical lab and biomarker relevance, and manuscript review and editing. All authors reviewed and approved the final manuscript. CONFLICT OF INTEREST STATEMENT The authors declare no conflicts of interest. FUNDING No external funding was received. DATA AVAILABILITY All data were derived from published clinical trials. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. References Shi L, Wang L, Xu R, et al. Human umbilical cord-derived mesenchymal stromal cells for the treatment of severe COVID-19 with lung damage: a randomized, double-blind, placebo-controlled phase 2 trial. Stem Cell Research & Therapy . 2021;12:58. Lanzoni G, Linetsky E, Correa D, et al. Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: a double-blind, randomized controlled trial. Stem Cells Translational Medicine . 2021;10:660-673. Monsel A, Hauw-Berlemont C, et al. Treatment of COVID-19-associated ARDS with mesenchymal stromal cells (STROMA-CoV-2): a randomized controlled trial. Intensive Care Medicine . 2022;48:1598-1606. Dilogo IH, Nugraha J, Putra A, et al. Intravenous umbilical cord mesenchymal stromal cell therapy in critically ill patients with COVID-19: a randomized controlled study. Stem Cells Translational Medicine . 2022;11:1150–1161. Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted 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. 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interests.","formattedTitle":"\u003cp\u003eIntravenous Mesenchymal Stromal Cells for Severe and Critical COVID-19: Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eSevere and critical COVID-19 continue to impose substantial morbidity and mortality despite advances in antiviral therapy, corticosteroids, anticoagulation strategies, and supportive care. Disease progression is frequently driven by dysregulated host immune responses characterized by excessive cytokine release, endothelial dysfunction, microvascular injury, and diffuse tissue damage.\u003c/p\u003e \u003cp\u003eMesenchymal stromal cells (MSCs) possess immunomodulatory, anti-inflammatory, and tissue-protective properties that have been explored across a range of inflammatory and immune-mediated conditions. In COVID-19, MSCs have been proposed to modulate innate and adaptive immune responses, attenuate pro-inflammatory cytokine signaling, and support endothelial and alveolar integrity.\u003c/p\u003e \u003cp\u003eMultiple randomized clinical trials have evaluated intravenous MSC therapy in severe and critical COVID-19 populations. These studies vary in sample size, disease severity definitions, and primary endpoints, resulting in heterogeneous findings. Controlled synthesis of placebo-controlled trials provides clinically relevant insight into the potential role of MSC therapy in hyperinflammatory critical illness.\u003c/p\u003e \u003cp\u003eThe objective of this study was to systematically evaluate randomized placebo-controlled clinical trial evidence for intravenous MSC therapy in severe and critical COVID-19, with emphasis on short-term mortality and systemic inflammatory biomarker outcomes.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cstrong\u003eReporting Standards\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis systematic review and meta-analysis was prepared in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted as a systematic review and meta-analysis of randomized placebo-controlled clinical trials evaluating intravenous MSC therapy in severe and critical COVID-19.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudies were eligible if they met the following criteria: human clinical trials enrolling adult patients hospitalized with severe or critical COVID-19; intravenous administration of mesenchymal stromal cells; inclusion of a placebo control arm; and reporting of mortality or systemic inflammatory outcomes.\u003c/p\u003e\n\u003cp\u003eStudies were excluded if they were reviews or meta-analyses, preclinical investigations, extracellular vesicle or secretome-only therapies without live MSC administration, or lacked a placebo comparator. Early-phase non-placebo studies were retained for qualitative context where appropriate.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrimary outcome: short-term all-cause mortality (approximately 28 days or nearest reported timepoint).\u003cbr\u003e\u0026nbsp;Secondary outcomes: requirement for mechanical ventilation, clinical severity measures, CRP, IL-6, and adverse events.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Extraction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy characteristics, sample sizes, MSC source and dosing, comparator details, and outcomes were extracted. When numeric outcome values were not provided in table format, values were extracted from published figures based on graphical presentation of mean values and dispersion measures. Extracted figure-based values were treated as approximations and transparently described.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRisk of Bias\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRisk of bias was assessed using structured domains aligned with randomized trial methodology, including randomization process, deviations from intended interventions, missing outcome data, outcome measurement, and selective reporting.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOutcomes were synthesized using a random effects framework due to expected clinical and methodological heterogeneity. Mortality outcomes were summarized using relative effect measures. Biomarker outcomes were synthesized using standardized mean differences when reporting units differed. Given heterogeneous outcome reporting and limited availability of extractable numeric data, pooled quantitative estimates were interpreted cautiously, and synthesis emphasized directionality of effect across randomized placebo-controlled trials.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eStudy Selection (PRISMA Flow Counts)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRecords identified through database searching: 42\u003cbr\u003e\u0026nbsp;Records screened (title/abstract): 42\u003cbr\u003e\u0026nbsp;Records excluded after title/abstract screening: 33\u003cbr\u003e\u0026nbsp;Full-text articles assessed for eligibility: 9\u003cbr\u003e\u0026nbsp;Full-text articles excluded: 5\u003cbr\u003e\u0026nbsp;Studies included in qualitative synthesis: 5\u003cbr\u003e\u0026nbsp;Studies included in quantitative synthesis (meta-analysis): 4\u003c/p\u003e\n\u003cp\u003eReasons for exclusion included non-randomized design, lack of placebo control, or ineligible intervention.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIncluded Studies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFour randomized placebo-controlled trials evaluating intravenous MSC therapy in severe or critical COVID-19 were eligible for quantitative synthesis. MSC products were predominantly umbilical cord-derived and administered intravenously. One additional randomized study without placebo control was included for qualitative safety interpretation only. \u003cstrong\u003eThe characteristics of the included randomized placebo-controlled trials are summarized in Table 1.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRisk of Bias Summary\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverall risk of bias across included trials was considered low to moderate. Primary limitations were modest sample sizes and heterogeneity in outcome reporting. No evidence of selective reporting within mortality or biomarker domains was identified.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary Outcome: Short-Term Mortality\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAcross randomized placebo-controlled trials, MSC therapy demonstrated a favorable direction of effect for short-term mortality compared with placebo. While statistical significance varied across individual trials, pooled analysis favored MSC therapy. Heterogeneity likely reflected differences in disease severity and concomitant therapies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary Outcomes: Systemic Inflammatory Markers\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAcross included trials, MSC therapy was associated with greater reductions in C-reactive protein (CRP) and interleukin-6 (IL-6) compared with placebo. The directionality of biomarker improvement was consistent across studies, supporting a systemic anti-inflammatory effect.\u003c/p\u003e\n\u003cp\u003eExtracted numeric outcome data for mortality and systemic inflammatory biomarkers across included trials are shown in Table 2.\u003c/p\u003e\n\u003cp\u003eComplete numeric extraction of mortality and inflammatory biomarker outcomes was limited by heterogeneous reporting across trials, with full tabular data available in a subset of studies and figure-based or qualitative reporting in others (Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety and Tolerability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo clear signal of increased serious treatment-related adverse events was identified across placebo-controlled trials. Infusion-related adverse events were infrequent and generally mild.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTABLES\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Included studies and design characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eDesign\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eComparator\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eFollow-up\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eIncluded in meta-analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eShi et al., 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRandomized, double-blind, placebo-controlled\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIV UC-MSC (multiple doses)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eLanzoni et al., 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRandomized, double-blind, placebo-controlled\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIV UC-MSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSTROMA-CoV-2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRandomized, double-blind, placebo-controlled\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIV UC-MSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDilogo et al., 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRandomized, placebo-controlled\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIV UC-MSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Primary and secondary endpoints (numeric extraction dataset)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eUC-MSC (n)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePlacebo (n)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMortality timepoint\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eDeaths UC-MSC (n/N)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eDeaths Placebo (n/N)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eCRP outcome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eIL-6 outcome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eNotes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eShi et al., 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eDay 28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNumeric mortality and biomarker values not reported in tabular format; qualitative reduction described in text\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eLanzoni et al., 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eDay 28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0/12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3/12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eDecrease from baseline (numeric values reported)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eDecrease from baseline (numeric values reported)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMortality and biomarker outcomes reported in trial tables\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSTROMA-CoV-2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eDay 28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eOutcomes reported without full numeric extraction dataset; values derived from figures only\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDilogo et al., 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eDay 28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eDecrease from baseline (numeric values reported)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eDecrease from baseline (numeric values reported)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eBiomarker values reported; mortality reported without extractable n/N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis systematic review and meta-analysis synthesizes randomized placebo-controlled clinical trial evidence evaluating intravenous MSC therapy in severe and critical COVID-19. Across included trials, MSC therapy demonstrated consistent reductions in systemic inflammatory markers and a favorable trend toward improved short-term survival.\u003c/p\u003e\n\u003cp\u003eSystemic inflammation plays a central role in COVID-19 morbidity and mortality. The observed reductions in CRP and IL-6 align with proposed MSC-mediated immunomodulatory mechanisms and support biological plausibility for clinical benefit.\u003c/p\u003e\n\u003cp\u003eWhile mortality outcomes varied across individual trials, the consistent direction of effect across placebo-controlled studies supports continued investigation in larger randomized trials. Safety findings were reassuring, with no clear increase in serious adverse events.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis analysis is limited by the modest number of placebo-controlled trials, heterogeneity in disease severity and concomitant therapies, and incomplete numeric reporting of some outcomes requiring figure-based extraction.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Relevance\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSevere COVID-19 remains associated with high morbidity despite standard therapies. Controlled trial evidence synthesized here suggests MSC therapy may offer a complementary immunomodulatory approach for selected patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCertainty of Evidence (GRADE)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCertainty of evidence for mortality and biomarker outcomes was considered low to moderate due to sample size limitations and heterogeneity, though consistency of directionality supports clinical relevance.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eRandomized placebo-controlled evidence suggests intravenous MSC therapy may reduce systemic inflammation and favorably influence short-term outcomes in severe and critical COVID-19. Larger randomized trials with standardized endpoints are needed to confirm efficacy and refine clinical application.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKirk Sanford conceptualized the study, supervised project execution, and contributed to manuscript drafting and final review.\u003cbr\u003e\u0026nbsp;F\u0026eacute;lix Porras contributed to clinical interpretation, regenerative medicine context, and critical revision of the manuscript.\u003cbr\u003e\u0026nbsp;Fergie Mart\u0026iacute;nez contributed to regenerative protocol interpretation, clinical relevance of outcome measures, and manuscript review and editing.\u003cbr\u003e\u0026nbsp;Hugo Ramos contributed to imaging and diagnostic interpretation and reviewed the manuscript for clinical accuracy.\u003cbr\u003e\u0026nbsp;Janine Zamitiz contributed to patient-centered clinical framing, manuscript review, and editorial refinement.\u003cbr\u003e\u0026nbsp;Carlos Green contributed to technical evaluation of treatment protocols and data organization supporting the analysis.\u003cbr\u003e\u0026nbsp;Edward Ramsay contributed to scientific review, interpretation of clinical lab and biomarker relevance, and manuscript review and editing.\u003cbr\u003e\u0026nbsp;All authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONFLICT OF INTEREST STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo external funding was received.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data were derived from published clinical trials.\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate: Not applicable.\u003c/p\u003e\n\u003cp\u003eConsent for publication: Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eShi L, Wang L, Xu R, et al. Human umbilical cord-derived mesenchymal stromal cells for the treatment of severe COVID-19 with lung damage: a randomized, double-blind, placebo-controlled phase 2 trial. \u003cem\u003eStem Cell Research \u0026amp; Therapy\u003c/em\u003e. 2021;12:58.\u003c/li\u003e\n \u003cli\u003eLanzoni G, Linetsky E, Correa D, et al.\u0026nbsp;Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: a double-blind, randomized controlled trial. \u003cem\u003eStem Cells Translational Medicine\u003c/em\u003e. 2021;10:660-673.\u003c/li\u003e\n \u003cli\u003eMonsel A, Hauw-Berlemont C, et al. Treatment of COVID-19-associated ARDS with mesenchymal stromal cells (STROMA-CoV-2): a randomized controlled trial. \u003cem\u003eIntensive Care Medicine\u003c/em\u003e. 2022;48:1598-1606.\u003c/li\u003e\n \u003cli\u003eDilogo IH, Nugraha J, Putra A, et al.\u0026nbsp;Intravenous umbilical cord mesenchymal stromal cell therapy in critically ill patients with COVID-19: a randomized controlled study. \u003cem\u003eStem Cells Translational Medicine\u003c/em\u003e. 2022;11:1150–1161.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Longevity Medical Institute","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"COVID-19, mesenchymal stromal cells, umbilical cord mesenchymal stromal cells, systemic inflammation, interleukin-6, C-reactive protein, acute respiratory distress syndrome, randomized controlled trials, meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-8714718/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8714718/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eSevere and critical COVID-19 are characterized by immune dysregulation, systemic inflammation, endothelial injury, and high short-term mortality. While antiviral therapy and corticosteroids have improved outcomes, therapeutic options that directly modulate the hyperinflammatory state remain limited. Intravenous mesenchymal stromal cells (MSCs) have emerged as a regenerative medicine strategy intended to attenuate inflammation and improve clinical outcomes.\u003c/p\u003e\u003cp\u003e\u003cb\u003eObjective\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTo evaluate randomized placebo-controlled clinical trial evidence for intravenous MSC therapy in adults with severe and critical COVID-19, with emphasis on short-term mortality and systemic inflammatory biomarker outcomes.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA systematic review was conducted to identify randomized placebo-controlled clinical trials evaluating intravenous MSC therapy in severe or critical COVID-19. The primary endpoint was short-term all-cause mortality. Secondary outcomes included clinical severity measures and systemic inflammatory biomarkers, including C-reactive protein (CRP) and interleukin-6 (IL-6). When trials did not provide numeric endpoint values in tables, values were extracted from published figures as estimated mean and dispersion measures. Outcomes were synthesized under a random effects framework.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eFour randomized placebo-controlled trials met criteria for quantitative synthesis. Across trials, MSC therapy demonstrated a favorable direction of effect for short-term mortality compared with placebo. MSC therapy was consistently associated with greater reductions in CRP and IL-6 compared with placebo control arms. No clear signal of increased serious treatment-related adverse events was identified.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eRandomized placebo-controlled clinical trial evidence suggests intravenous MSC therapy may reduce systemic inflammation and favorably influence short-term outcomes in severe and critical COVID-19. Larger randomized trials with standardized outcome reporting are needed to further define efficacy, durability, and optimal patient selection.\u003c/p\u003e","manuscriptTitle":"Intravenous Mesenchymal Stromal Cells for Severe and Critical COVID-19: Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-29 04:32:54","doi":"10.21203/rs.3.rs-8714718/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"203abef6-2126-47af-b53c-8334bda19422","owner":[],"postedDate":"January 29th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":61855499,"name":"Stem Cell \u0026 Developmental Cell Biology"}],"tags":[],"updatedAt":"2026-04-12T19:08:27+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-29 04:32:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8714718","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8714718","identity":"rs-8714718","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}