{"paper_id":"cf21ffd2-a096-4f1d-88a5-6fde7072ee96","body_text":"Abstract\nBackground\nStem cell-based therapies have emerged as a promising approach for endometriosis due to their regenerative and immunomodulatory properties. Although numerous preclinical studies have reported beneficial effects, no systematic synthesis has yet evaluated their impact, the models employed and associated biomarkers. Therefore, the aim of this systematic review is to synthesise all available preclinical evidence (both in vitro and in vivo) assessing stem cell-based therapies and stem cell-derived products in experimental models of endometriosis.\nMethods\nFollowing PRISMA guidelines, PubMed, Scopus and Web of Science were searched from 1 January 2015 up to 11 February 2025. Preclinical studies (in vitro and in vivo) evaluating stem cell-based therapies in experimental models of endometriosis were included. Data were extracted regarding the models employed, cell sources, analysed biomarkers and reported cellular outcomes.\nResults\nTwenty preclinical studies were included, employing a wide range of in vitro models (most commonly endometriotic cells) and predominantly murine in vivo models induced by intraperitoneal injection of uterine tissue. Adipose-derived stem cells (ADSCs) and bone marrow-mesenchymal stem cells (BMMSCs) were the most frequently investigated cell sources. Across the studies, VEGFA, TNFA, metalloproteinases (MMPs) and components of the PI3K/AKT/mTOR pathway were the most consistently analysed biomarkers, primarily assessed by PCR and immunohistochemistry. Overall, 72 of the 92 reported outcomes were positive, with ADSCs demonstrating the most pronounced therapeutic effects and being characterised by their immunomodulatory, anti-inflammatory and regenerative activity. Negative or neutral findings, such as increased cellular adhesion and invasion, were limited and largely associated with ADSCs and umbilical cord mesenchymal stem cells (UCMSCs).\nConclusions\nStem cell-based therapies demonstrate promising effects in experimental endometriosis, with most studies reporting improvements in lesion characteristics and inflammatory pathways. However, substantial variability in models, cell types and outcomes limits the strength of current evidence. More standardised and rigorous preclinical research is needed to confirm these findings and support the translation of stem cell therapy-based approaches into future clinical practice.\nSimilar content being viewed by others\nData availability\nThe datasets obtained during the present review are available from the corresponding author upon reasonable request.\nAbbreviations\n- ADSCs:\n-\nAdipose-derived stem cells\n- BMMSCs:\n-\nBone marrow mesenchymal stem cells\n- COX-2:\n-\nCyclooxygenase-2\n- ELISA:\n-\nEnzyme-linked Immunosorbent Assay\n- eMSCs:\n-\nEndometrial mesenchymal stem cells\n- ERβ:\n-\nOestrogen receptor beta\n- GnRH:\n-\nGonadotrophin-releasing hormone\n- HUVEC:\n-\nHuman umbilical vein endothelial cells\n- IF:\n-\nImmunofluorescence\n- IHC:\n-\nImmunohistochemistry\n- MenSCs:\n-\nMenstrual blood-derived mesenchymal stem cells\n- MMPs :\n-\nMetalloproteinases\n- NO:\n-\nNitric oxide\n- N.S.:\n-\nNumber of studies\n- NSAIDs:\n-\nNon-steroidal anti-inflammatory drugs\n- PCR:\n-\nPolymerase Chain Reaction\n- PRISMA:\n-\nPreferred Reporting Items for Systematic Reviews and Meta-Analyses\n- TAC:\n-\nTotal antioxidant capacity\n- TUNEL:\n-\nTerminal deoxynucleotidyl transferase-mediated dUTP nick end labelling\n- UCMSCs:\n-\nUmbilical cord mesenchymal stem cells\n- WB:\n-\nWestern blotting\n- WJSCs:\n-\nWharton's jelly stem cells\nReferences\nWHO. 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JBI Evid Synth. 2024;22:389–93. https://doi.org/10.11124/JBIES-23-00463.\nAcknowledgements\nThe authors would like to sincerely thank Nuria González for her invaluable assistance in the design, preparation, and improvement of the figures included in this manuscript.\nFunding\nThis research was funded by: Plan Complementario de Biotecnología Aplicada a la Salud, co-financed by the Ministry of Science and Innovation with funds from the European Union's NextGenerationEU initiative; by Instituto de Salud Carlos III (ISCIII) through RICORS/TERAV (RD21/0017/0014) supported by European Union's NextGenerationEU and Recovery, Transformation and Resilience Plan, by Consejería de Educación, Ciencia y Formación Profesional of the Junta de Extremadura (GR24210), co-funded by the European Regional Development Fund (ERDF) and with support to I. Suárez-Carrasco from MAFRESA, EL IBÉRICO DE CONFIANZA SL.\nAuthor information\nAuthors and Affiliations\nContributions\nI. Suárez-Carrasco and E. López: conceptualisation, methodology, literature search, data extraction and formal analysis. M.A. De Pedro, M. Pulido and V. Álvarez: writing (review and editing). F.M. Sánchez-Margallo: supervision, project administration and funding acquisition. 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