The effectiveness of stem cell‑derived extracellular vesicles therapy for intrauterine adhesions: a meta-analysis of preclinical studies

Sun et al. Reproductive Biology and Endocrinology https://doi.org/10.1186/s12958-025-01448-2 Reproductive Biology and Endocrinology (2025) 23:117 Open Access RESEARCH The effectiveness of stem cell‑derived extracellular vesicles therapy for intrauterine adhesions: a meta-analysis of preclinical studies Yuanyuan Sun1,2†, Yan Luo1,2†, Jinyao Ning1,2†, Yitong Chai1,2, Jingjing Chen1,2, Fen Xiao3, Ge Li1,2, Xu Zhou1,2, Fen Tian1,2, Bin Xu1,2, Qiong Zhang1,2, Hankun Su1,2, Jing Zhao1,2, Yanping Li1,2 and Hui Li1,2* Abstract Background The therapeutic potential of stem cell-derived extracellular vesicles (EVs) for intrauterine adhesions (IUA) has attracted increasing preclinical investigation, yet a comprehensive and up-to-date meta-analysis is currently lacking. Before moving forward with clinical applications, it is essential to fully understand the impact of stem cellderived EVs on IUA. Methods PubMed, EMBASE, Cochrane Library, Web of Science were searched up to May 19th 2025. Trial sequential analysis was conducted to evaluate outcomes, while sensitivity analysis and publication bias assessment were conducted using Stata 14. Results Across 26 studies (899 animals), our analyses have uncovered several important findings as the following: stem cell-derived EVs significantly improved the number of endometrial glands (SMD = 3.78; 95% CI: 2.62 ~ 4.93; P < 0.00001); endometrial thickness (SMD = 2.65; 95% CI: 1.90 ~ 3.40; P < 0.00001) and the number of embryos (SMD = 2.00; 95% CI: 1.02 ~ 2.97; P = 0.0004); fibrosis reduction (SMD = -3.25; 95% CI: -4.24~ -2.26; P < 0.00001) in IUA animal models. EVs downregulated fibrosis markers (TGF-β1, α-SMA, Col-1) and upregulated vascularization (VEGF) and proliferation (Ki67) genes. Conclusions Stem cell-derived EVs demonstrate safety and efficacy in treating IUA animal models, with potential improvements in fertility outcomes. Keywords Intrauterine adhesions, Extracellular vesicles, Meta-analysis, Trial sequential analysis † Yuanyuan Sun MD, Yan Luo MD and Jinyao Ning MD contributed equally to this work and share the first authorship. *Correspondence: Hui Li 1 Department of Reproductive Medicine, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province 410008, China 2 Clinical Research Center for Women’s Reproductive Health in Hunan Province, Changsha, Hunan Province 410008, China 3 Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan Province 410011, China © The Author(s) 2025. 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To view a copy of this licence, visit http://creati vecommons.org/licenses/by-nc-nd/4.0/. Sun et al. Reproductive Biology and Endocrinology (2025) 23:117 Introduction Intrauterine adhesion (IUA), or Asherman’s syndrome, can be caused by infections, mechanical injuries, and excessive stem cell loss from the endometrial basal layer, leading to uterine cavity adhesions or atresia [1]. This condition presents with clinical manifestations such as scanty menstruation, amenorrhea, cyclic abdominal pain, primary or secondary infertility, and recurrent miscarriages [1, 2]. Studies have shown that the incidence of IUA after abortion and induced abortion in early pregnancy can be as high as 21% and 35% [2], and the incidence of IUA and thin endometrium due to repeated abortions is about 53.3% [3]. Currently, the main procedure for IUA treatments includes: surgical separation of adherent tissues, restoration of uterine anatomy, placement of physical barriers, prevention of re-adhesion, and estrogen stimulation of endothelial regeneration [4, 5]. At present, the recurrence rate of postoperative adhesions in patients with moderate-to-severe IUA is still high, up to 62.5%, while the overall pregnancy rate after natural pregnancy and assisted reproduction techniques is only 22.5-33.3% [6]. Given such huge difference in statistics, it is crucial to investigate the dual repair strategies and mechanisms of the damaged endometrium, addressing both structural and functional aspects. In recent years, the infusion of stem cells or stem cell-derived factors into the uterus has become a new approach to be incorporated in the clinical treatment of IUA [1, 7]. A large number of studies have shown that stem cells can ameliorate endometrial damage through paracrine effects [8, 9], in which the extracellular vesicles (EVs) secreted by stem cells play a vital role in carrying and transferring proteins, lipids, RNA, metabolites, growth factors, and cytokines, and contribute significantly to cell-cell communication, also have anti-inflammatory, anti-fibrotic, and tissue regeneration-promoting potentials, and thus have been considered as potential new therapies for the treatment of IUA [10–12]. Compared to stem cells, Stem cell-derived EVs not only retain similar functions but also exhibit greater biological stability, lower immunogenicity, and easier availability, making them a promising alternative therapy. The uterine cavity communicates with the vagina via the cervical canal, which poses a significant challenge for intrauterine therapeutics as injected bioactive solutions are prone to leakage through the cervical canal, thereby compromising treatment efficacy. Furthermore, EVs undergo rapid clearance by the mononuclear phagocyte system in vivo, exhibiting a short half-life that necessitates the use of biomaterial-based delivery systems to prolong their retention [13, 14]. Hydrogel, a three-dimensional network structure formed by cross-linking hydrophilic polymer chains, is very similar to the extracellular matrix environment, and has been widely used for drug Page 2 of 20 sustained release due to its drug-carrying structure and its good biocompatibility [15, 16]. However, significant differences exist in the sources of EVs (such as embryonic stem cells, mesenchymal stromal cells, etc.), the routes of administration, and the concentrations used, all of which can impact therapeutic efficacy [17–19]. There is a need for more comprehensive reviews and meta-analyses to unde (...truncated)