Steps towards the clinical application of endometrial and menstrual fluid mesenchymal stem cells for the treatment of gynecological disorders

Alexander Sadiasa, Jerome A. Werkmeister, Shanti Gurung, Caroline E. Gargett
In: Expert Opinion on Biological Therapy · 2025 · vol. 25(3) , pp. 285–307 · doi:10.1080/14712598.2025.2465826 · PMID:39925343 · W4407341042
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This review updates research on endometrial and menstrual fluid mesenchymal stem cells, highlighting their therapeutic potential via paracrine activity for gynecological diseases and the need for standardized protocols and purification methods.

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Abstract

INTRODUCTION: The human endometrium is a highly regenerative tissue that contains mesenchymal stem/stromal cells (MSCs). These MSCs are sourced via office-based biopsies and menstrual fluid, providing a less invasive and readily available option for cell-based therapies. This review provides an update on endometrial-derived MSCs as a treatment option for gynecological diseases. AREAS COVERED: This narrative review covers the characterization and therapeutic mechanisms of endometrium biopsy-derived MSCs (eMSCs) and menstrual fluid-derived mesenchymal stromal cells (MenSCs), highlighting similarities and differences. It also covers studies of their application in preclinical animal models and in clinical trials as potential cell-based therapies for gynecological diseases. EXPERT OPINION: eMSCs and MenSCs from a homologous tissue source have the potential to promote regenerative activity as a treatment for gynecological diseases. Both eMSCs and MenSCs demonstrate therapeutic benefits through their paracrine activity in tissue regeneration, immunomodulation, angiogenesis, and mitigating fibrosis. Further research is essential to establish standardized isolation and characterization protocols, particularly for heterogeneous MenSCs, and to fully understand their mechanisms of action. Implementing SUSD2 magnetic bead sorting for purifying eMSCs from endometrial tissues and menstrual fluid is crucial for their use in future cell-based therapies. Optimization of production, storage, and delivery methods will maximize their therapeutic effectiveness.
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ABSTRACT Introduction The human endometrium is a highly regenerative tissue that contains mesenchymal stem/stromal cells (MSCs). These MSCs are sourced via office-based biopsies and menstrual fluid, providing a less invasive and readily available option for cell-based therapies. This review provides an update on endometrial-derived MSCs as a treatment option for gynecological diseases. Areas covered This narrative review covers the characterization and therapeutic mechanisms of endometrium biopsy-derived MSCs (eMSCs) and menstrual fluid-derived mesenchymal stromal cells (MenSCs), highlighting similarities and differences. It also covers studies of their application in preclinical animal models and in clinical trials as potential cell-based therapies for gynecological diseases. Expert opinion eMSCs and MenSCs from a homologous tissue source have the potential to promote regenerative activity as a treatment for gynecological diseases. Both eMSCs and MenSCs demonstrate therapeutic benefits through their paracrine activity in tissue regeneration, immunomodulation, angiogenesis, and mitigating fibrosis. Further research is essential to establish standardized isolation and characterization protocols, particularly for heterogeneous MenSCs, and to fully understand their mechanisms of action. Implementing SUSD2 magnetic bead sorting for purifying eMSCs from endometrial tissues and menstrual fluid is crucial for their use in future cell-based therapies. Optimization of production, storage, and delivery methods will maximize their therapeutic effectiveness. Article highlights MSC can be obtained from human endometrium non-invasively from endometrial biopsies and menstrual fluid, a source that regenerates monthly, allowing multiple collections from the same donor. A single surface marker, SUSD2, provides a simple isolation protocol for purifying mesenchymal stem cells (MSCs), including endometrial MSCs (eMSCs), using magnetic bead sorting, which preserves cell viability and yields perivascular MSCs. This approach is preferable for clinical applications compared to complex, fluorescence-activated cell sorting (FACS) using multiple markers and requires expensive equipment (flow cytometer). MenSCs, cultured directly from menstrual fluid similar to BM-MSC, are heterogeneous and donor-dependent, leading to variability in potency that can yield unexpected therapeutic results. The isolation protocol for enriching MSCs from menstrual fluids needs refinement for better therapeutic efficacy. The therapeutic potential of eMSCs and MenSCs has been shown in various gynecological disease models: intrauterine adhesions (IUA), Asherman’s syndrome, and thin unresponsive endometrium by stimulating endometrial regeneration and improving endometrial function, and in pelvic organ prolapse by immunomodulation of the foreign body response to implanted meshes. Small extracellular vesicles (sEVs) from eMSCs and MenSCs are promising off-the-shelf therapeutic agents due to their stability, low immunogenicity, and ability to target specific cells, influencing inflammation and tissue repair. To date, no clinical study has utilized SUSD2+ eMSCs, while MenSCs have been investigated in several clinical trials for the treatment of diseases such as COVID-19 and primary ovarian insufficiency. The therapeutic properties and clinical effectivities of MenSCs can be further improved by optimizing isolation protocols, culture conditions, and delivery methods. Both eMSCs and MenSCs could improve outcomes by utilizing the latest technologies such as genetic manipulation. Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Reviewer disclosures Peer reviewers on this manuscript have no relevant financial or other relationships to disclose. Author contributions A Sadiasa: literature search, designing – tables and figures, writing – original draft, review, and editing. JA Werkmeister: supervision and Writing – review and editing. S Gurung: conceptualization, supervision, and writing – review and editing. CE Gargett: funding acquisition, conceptualization, supervision, and writing – review and editing. All authors contributed to the article and approved the submitted version. Acknowledgments The graphical abstract was created in BioRender. Sadiasa, A. (2025) https://BioRender.com/k04z500.

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