Mesenchymal Stem Cell-Derived Exosomes for the Treatment of Premature Ovarian Insufficiency: Mechanism, Application and Clinical Translation Prospects

Lu Liu; Limei Yu

doi:10.54097/e99drx83

Authors

Lu Liu
Limei Yu

DOI:

https://doi.org/10.54097/e99drx83

Keywords:

Premature Ovarian Insufficiency, Mesenchymal Stem Cells, Exosomes, Preclinical Research

Abstract

Premature ovarian insufficiency (POI) refers to a reproductive endocrine disease in which ovarian function is impaired in women before the age of 40, which seriously affects the quality of life of patients and increases their psychological and socioeconomic burden. At present, there are still certain limitations in the treatment of premature ovarian insufficiency, and none of them can fundamentally restore the patient's ovarian function. This forces people to find more effective ways to treat POI so that patients can achieve clinical pregnancy after effective treatment. Mesenchymal stem cells (MSCs) are a type of multipotent stem cells capable of self-renewal and multidirectional differentiation. A large number of studies have shown that exosomes (Exo) secreted by mesenchymal stem cells can regulate the ovarian microenvironment through multiple mechanisms and play an important role in improving the ovarian function of POI mice. In this review, we mainly discuss the biogenesis of Exo, the characteristics of MSCs-derived Exo, their role in the treatment of POI, and related preclinical studies, so as to provide some new ideas for the clinical application of MSCs-derived Exo in the treatment of POI.

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References

[1] TOURAINE P, CHABBERT-BUFFET N, PLU-BUREAU G, et al. Premature ovarian insufficiency [J]. Nat Rev Dis Primers, 2024, 10(1): 63.

[2] FU X, HE Y, WANG X, et al. Overexpression of miR-21 in stem cells improves ovarian structure and function in rats with chemotherapy-induced ovarian damage by targeting PDCD4 and PTEN to inhibit granulosa cell apoptosis [J]. Stem Cell Res Ther, 2017, 8(1): 187.

[3] HUANG C, GUO T, QIN Y. Meiotic Recombination Defects and Premature Ovarian Insufficiency [J]. Front Cell Dev Biol, 2021, 9: 652407.

[4] BARROS F, CARVALHO F, BARROS A, et al. Premature ovarian insufficiency: clinical orientations for genetic testing and genetic counseling [J]. Porto Biomed J, 2020, 5(3): e62.

[5] JIAO X, ZHANG H, KE H, et al. Premature Ovarian Insufficiency: Phenotypic Characterization Within Different Etiologies [J]. J Clin Endocrinol Metab, 2017, 102(7): 2281-90.

[6] HAMMOND J, MARCZAK M. Women's experiences of premature ovarian insufficiency: a thematic synthesis [J]. Psychol Health, 2025, 40(2): 192-216.

[7] LI M, ZHU Y, WEI J, et al. The global prevalence of premature ovarian insufficiency: a systematic review and meta-analysis [J]. Climacteric, 2023, 26(2): 95-102.

[8] VAN DORP W, HAUPT R, ANDERSON R A, et al. Reproductive Function and Outcomes in Female Survivors of Childhood, Adolescent, and Young Adult Cancer: A Review [J]. J Clin Oncol, 2018, 36(21): 2169-80.

[9] ANDERSON R A, AMANT F, BRAAT D, et al. ESHRE guideline: female fertility preservation [J]. Hum Reprod Open, 2020, 2020(4): hoaa052.

[10] WANG J, LIU W, YU D, et al. Research Progress on the Treatment of Premature Ovarian Failure Using Mesenchymal Stem Cells: A Literature Review [J]. Front Cell Dev Biol, 2021, 9: 749822.

[11] MO J, HU H, LI P, et al. Human hair follicle-derived mesenchymal stem cells improve ovarian function in cyclophosphamide-induced POF mice [J]. Stem Cell Res Ther, 2025, 16(1): 67.

[12] SUN L, LI D, SONG K, et al. Exosomes derived from human umbilical cord mesenchymal stem cells protect against cisplatin-induced ovarian granulosa cell stress and apoptosis in vitro [J]. Sci Rep, 2017, 7(1): 2552.

[13] HELDRING N, MäGER I, WOOD M J, et al. Therapeutic Potential of Multipotent Mesenchymal Stromal Cells and Their Extracellular Vesicles [J]. Hum Gene Ther, 2015, 26(8): 506-17.

[14] LOTFY A, ABOQUELLA N M, WANG H. Mesenchymal stromal/stem cell (MSC)-derived exosomes in clinical trials [J]. Stem Cell Res Ther, 2023, 14(1): 66.

[15] PU X, ZHANG L, ZHANG P, et al. Human UC-MSC-derived exosomes facilitate ovarian renovation in rats with chemotherapy-induced premature ovarian insufficiency [J]. Front Endocrinol (Lausanne), 2023, 14: 1205901.

[16] LU Y, WEI Y, SHEN X, et al. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles improve ovarian function in rats with primary ovarian insufficiency by carrying miR-145-5p [J]. J Reprod Immunol, 2023, 158: 103971.

[17] QU Q, LIU L, CUI Y, et al. miR-126-3p containing exosomes derived from human umbilical cord mesenchymal stem cells promote angiogenesis and attenuate ovarian granulosa cell apoptosis in a preclinical rat model of premature ovarian failure [J]. Stem Cell Res Ther, 2022, 13(1): 352.

[18] IBRAHIM A, MARBáN E. Exosomes: Fundamental Biology and Roles in Cardiovascular Physiology [J]. Annu Rev Physiol, 2016, 78: 67-83.

[19] LIN Z, WU Y, XU Y, et al. Mesenchymal stem cell-derived exosomes in cancer therapy resistance: recent advances and therapeutic potential [J]. Mol Cancer, 2022, 21(1): 179.

[20] BAIETTI M F, ZHANG Z, MORTIER E, et al. Syndecan-syntenin-ALIX regulates the biogenesis of exosomes [J]. Nat Cell Biol, 2012, 14(7): 677-85.

[21] LARIOS J, MERCIER V, ROUX A, et al. ALIX- and ESCRT-III-dependent sorting of tetraspanins to exosomes [J]. J Cell Biol, 2020, 219(3).

[22] WEI D, ZHAN W, GAO Y, et al. RAB31 marks and controls an ESCRT-independent exosome pathway [J]. Cell Res, 2021, 31(2): 157-77.

[23] YEO R W, LAI R C, ZHANG B, et al. Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery [J]. Adv Drug Deliv Rev, 2013, 65(3): 336-41.

[24] LAI R C, YEO R W, LIM S K. Mesenchymal stem cell exosomes [J]. Semin Cell Dev Biol, 2015, 40: 82-8.

[25] ZHAO J, LI Y, JIA R, et al. Mesenchymal Stem Cells-Derived Exosomes as Dexamethasone Delivery Vehicles for Autoimmune Hepatitis Therapy [J]. Front Bioeng Biotechnol, 2021, 9: 650376.

[26] BI Y, QIAO X, LIU Q, et al. Systemic proteomics and miRNA profile analysis of exosomes derived from human pluripotent stem cells [J]. Stem Cell Res Ther, 2022, 13(1): 449.

[27] ASSUNçãO-SILVA R C, MENDES-PINHEIRO B, PATRíCIO P, et al. Exploiting the impact of the secretome of MSCs isolated from different tissue sources on neuronal differentiation and axonal growth [J]. Biochimie, 2018, 155: 83-91.

[28] HADE M D, SUIRE C N, SUO Z. Mesenchymal Stem Cell-Derived Exosomes: Applications in Regenerative Medicine [J]. Cells, 2021, 10(8).

[29] LIU T, ZHANG Q, ZHANG J, et al. EVmiRNA: a database of miRNA profiling in extracellular vesicles [J]. Nucleic Acids Res, 2019, 47(D1): D89-d93.

[30] SUN B, MA Y, WANG F, et al. miR-644-5p carried by bone mesenchymal stem cell-derived exosomes targets regulation of p53 to inhibit ovarian granulosa cell apoptosis [J]. Stem Cell Res Ther, 2019, 10(1): 360.

[31] YANG M, LIN L, SHA C, et al. Bone marrow mesenchymal stem cell-derived exosomal miR-144-5p improves rat ovarian function after chemotherapy-induced ovarian failure by targeting PTEN [J]. Lab Invest, 2020, 100(3): 342-52.

[32] XING J, ZHANG M, ZHAO S, et al. EIF4A3-Induced Exosomal circLRRC8A Alleviates Granulosa Cells Senescence Via the miR-125a-3p/NFE2L1 axis [J]. Stem Cell Rev Rep, 2023, 19(6): 1994-2012.

[33] PARK H S, SEOK J, CETIN E, et al. Fertility protection: a novel approach using pretreatment with mesenchymal stem cell exosomes to prevent chemotherapy-induced ovarian damage in a mouse model [J]. Am J Obstet Gynecol, 2024.

[34] LI Z, ZHANG M, ZHENG J, et al. Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Improve Ovarian Function and Proliferation of Premature Ovarian Insufficiency by Regulating the Hippo Signaling Pathway [J]. Front Endocrinol (Lausanne), 2021, 12: 711902.

[35] TAN Q, XIA D, YING X. miR-29a in Exosomes from Bone Marrow Mesenchymal Stem Cells Inhibit Fibrosis during Endometrial Repair of Intrauterine Adhesion [J]. Int J Stem Cells, 2020, 13(3): 414-23.

[36] GENG Z, CHEN H, ZOU G, et al. Human Amniotic Fluid Mesenchymal Stem Cell-Derived Exosomes Inhibit Apoptosis in Ovarian Granulosa Cell via miR-369-3p/YAF2/PDCD5/p53 Pathway [J]. Oxid Med Cell Longev, 2022, 2022: 3695848.

[37] ZHANG L, MA Y, XIE X, et al. Human Pluripotent Stem Cell-Mesenchymal Stem Cell-Derived Exosomes Promote Ovarian Granulosa Cell Proliferation and Attenuate Cell Apoptosis Induced by Cyclophosphamide in a POI-like Mouse Model [J]. Molecules, 2023, 28(5).

[38] YANG W, ZHANG J, XU B, et al. HucMSC-Derived Exosomes Mitigate the Age-Related Retardation of Fertility in Female Mice [J]. Mol Ther, 2020, 28(4): 1200-13.

[39] ZHANG S, HUANG B, SU P, et al. Concentrated exosomes from menstrual blood-derived stromal cells improves ovarian activity in a rat model of premature ovarian insufficiency [J]. Stem Cell Res Ther, 2021, 12(1): 178.

[40] ZHU X, LI W, LU M, et al. M(6)A demethylase FTO-stabilized exosomal circBRCA1 alleviates oxidative stress-induced granulosa cell damage via the miR-642a-5p/FOXO1 axis [J]. J Nanobiotechnology, 2024, 22(1): 367.

[41] ZHOU Y, HUANG J, ZENG L, et al. Human mesenchymal stem cells derived exosomes improve ovarian function in chemotherapy-induced premature ovarian insufficiency mice by inhibiting ferroptosis through Nrf2/GPX4 pathway [J]. J Ovarian Res, 2024, 17(1): 80.

[42] HU X, HE C, ZHANG L, et al. Mesenchymal stem cell-derived exosomes attenuate DNA damage response induced by cisplatin and bleomycin [J]. Mutat Res Genet Toxicol Environ Mutagen, 2023, 889: 503651.

[43] DING C, ZHU L, SHEN H, et al. Exosomal miRNA-17-5p derived from human umbilical cord mesenchymal stem cells improves ovarian function in premature ovarian insufficiency by regulating SIRT7 [J]. Stem Cells, 2020, 38(9): 1137-48.

[44] ESLAMI N, BAHREHBAR K, ESFANDIARI F, et al. Regenerative potential of different extracellular vesicle subpopulations derived from clonal mesenchymal stem cells in a mouse model of chemotherapy-induced premature ovarian failure [J]. Life Sci, 2023, 321: 121536.

[45] IGBOELI P, EL ANDALOUSSI A, SHEIKH U, et al. Intraovarian injection of autologous human mesenchymal stem cells increases estrogen production and reduces menopausal symptoms in women with premature ovarian failure: two case reports and a review of the literature [J]. J Med Case Rep, 2020, 14(1): 108.

[46] MASHAYEKHI M, MIRZADEH E, CHEKINI Z, et al. Evaluation of safety, feasibility and efficacy of intra-ovarian transplantation of autologous adipose derived mesenchymal stromal cells in idiopathic premature ovarian failure patients: non-randomized clinical trial, phase I, first in human [J]. J Ovarian Res, 2021, 14(1): 5.

[47] ZAFARDOUST S, KAZEMNEJAD S, DARZI M, et al. Improvement of Pregnancy Rate and Live Birth Rate in Poor Ovarian Responders by Intraovarian Administration of Autologous Menstrual Blood Derived- Mesenchymal Stromal Cells: Phase I/II Clinical Trial [J]. Stem Cell Rev Rep, 2020, 16(4): 755-63.