Advances in Skin, Wound and Tissue Repair

en Beyond the Cells: MSC-Derived Conditioned Medium as a Novel Therapeutic Paradigm for Endometriosis عمومى General مروری Review Endometriosis is a chronic, estrogen‑dependent disorder affecting approximately 10% of reproductive‑aged women, characterized by the growth of endometrial‑like tissue outside the uterus. This ectopic tissue creates a pathologic microenvironment driven by persistent NF‑κB activation, elevated pro‑inflammatory cytokines (IL‑1β, IL‑6, TNF‑α), increased COX‑2/PGE2 signaling, and high oxidative stress—collectively promoting angiogenesis, fibrosis, and apoptosis resistance. Conventional treatments face limitations including high recurrence rates and adverse effects, driving interest in cell‑free regenerative strategies. Mesenchymal stem cell (MSC)‑derived conditioned medium, particularly its exosomal fraction, has emerged as a promising off‑the‑shelf therapeutic platform. This review synthesizes recent evidence (2023–2025) on the mechanisms and preclinical efficacy of the MSC secretome in endometriosis. The MSC secretome exerts multi‑target effects: it suppresses NF‑κB/COX‑2/PGE2 signaling and reduces IL‑1β, IL‑6, and TNF‑α, reversing the inflammatory niche. Anti‑angiogenic actions involve the miR‑21‑5p/TIMP3/PI3K/Akt/mTOR pathway. Anti‑fibrotic effects are mediated via miR‑140‑3p/FOXP1/Smad and lncRNA IGF2R/miR‑143‑5p/AQP8 axes. Additionally, the secretome reactivates intrinsic mitochondrial apoptosis (increased Bax/Bcl‑2 ratio and caspase‑3/9) while downregulating proliferative markers such as Ki‑67 and Cyclin D1. Preclinical studies demonstrate up to 75% reduction in lesion volume in murine models. Compared with live cell therapy, exosomes offer low immunogenicity, lyophilization stability, scalable GMP‑compliant production, and inherent homing capacity. Despite remaining standardization challenges, MSC‑derived exosomes represent a novel non‑hormonal, fertility‑sparing intervention with transformative potential for endometriosis management. Endometriosis, Mesenchymal stem cells, Secretome, Exosomes, NF κB, Angiogenesis, Apoptosis 1 10 http://icml.ir/browse.php?a_code=A-10-684-1&slc_lang=en&sid=1 Samaneh Hamedi samanehh1220@gmail.com 1050031947532846005681 1050031947532846005681 Yes Department of Cell and Developmental Biology, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran Melika Habibzadeh Shojaee habibzadeh.melika@gmail.com 1050031947532846005682 1050031947532846005682 No Department of Cell and Developmental Biology, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran Ashraf Moeini Ashraf.moeini@gmail.com 1050031947532846005683 1050031947532846005683 No Department of Gynecology and Obstetrics, Arash Women's Hospital, Tehran University of Medical Sciences, Tehran, Iran Nahid Nasiri anahid.1333@yahoo.com 1050031947532846005684 1050031947532846005684 No Department of Medical Laser, Medical Laser Research Center, Yara Institute, ACECR, Tehran, Iran Maryam Hafezi maryamhafezi90@yahoo.com 1050031947532846005685 1050031947532846005685 No Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran