间充质干细胞治疗卵巢早衰的研究进展

doi:10.12280/gjszjk.20260115

摘要/Abstract

摘要：

卵巢早衰（premature ovarian failure，POF）是导致女性不孕及远期健康损害的重要内分泌疾病，传统治疗效果有限。间充质干细胞（mesenchymal stem cell，MSC）凭借多向分化、旁分泌、免疫调节及归巢特性，为POF治疗提供了新策略。不同组织来源的MSC（脐带、骨髓、经血、脂肪、羊膜、尿液等）在疗效与获取便捷性上各具优势。通过基因工程修饰、预处理、细胞外囊泡及生物材料支架联合等策略，可进一步提升MSC的修复效能。临床研究已初步验证了MSC的安全性与可行性，但仍面临标准化、疗效异质性与长期安全性等挑战，未来将向精准化治疗、“无细胞”疗法、卵巢类器官构建及多学科融合方向发展，以推动临床转化。

关键词: 原发性卵巢功能不全, 间质干细胞, 间质干细胞移植, 再生医学, 卵巢早衰

Abstract:

Premature ovarian failure (POF) is a major endocrine disorder leading to female infertility and long?term health risks, with limited efficacy of conventional therapies. Mesenchymal stem cells (MSCs) offer new therapeutic avenues for POF due to the multidirectional differentiation, paracrine activity, immunomodulation, and homing capacity. MSCs from various tissue sources (umbilical cord, bone marrow, menstrual blood, adipose tissue, amnion, urine, etc.) have distinct advantages in efficacy and accessibility. Strategies including genetic engineering modification, preconditioning, extracellular vesicles, and biomaterial-based scaffolds further enhance the reparative potential of MSCs. Preliminary clinical studies have demonstrated the safety and feasibility of MSCs, yet challenges remain, such as standardization, heterogeneous efficacy, and long-term safety. Future directions, such as precision therapy, cell-free approaches, ovarian organoid construction and interdisciplinary integration, will promote the clinical translation.

Key words: Primary ovarian insufficiency, Mesenchymal stem cells, Mesenchymal stem cell transplantation, Regenerative medicine, Premature ovarian failure

李欢, 杨丽娟, 胡硕楠, 李琳, 熊青. 间充质干细胞治疗卵巢早衰的研究进展[J]. 国际生殖健康/计划生育杂志, 2026, 45(4): 331-335.

LI Huan, YANG Li-juan, HU Shuo-nan, LI Lin, XIONG Qing. Research Progress on Mesenchymal Stem Cells in the Treatment of Premature Ovarian Failure[J]. Journal of International Reproductive Health/Family Planning, 2026, 45(4): 331-335.

参考文献 41

[1]	Takahashi A, Yousif A, Hong L, et al. Premature ovarian insufficiency: pathogenesis and therapeutic potential of mesenchymal stem cell[J]. J Mol Med(Berl), 2021, 99(5):637-650. doi: 10.1007/ s00109-021-02055-5.
[2]	Shi YQ, Zhu XT, Zhang SN, et al. Premature ovarian insufficiency: a review on the role of oxidative stress and the application of antioxidants[J]. Front Endocrinol(Lausanne), 2023, 14:1172481. doi: 10.3389/fendo.2023.1172481.
[3]	Vijayalakshmi SR, Shagun A. Genetics of premature ovarian failure[J]. Genet Clin, 2018, 11(2): 10-17.
[4]	Panay N, Anderson RA, Bennie A, et al. Evidence-based guideline: premature ovarian insufficiency[J]. Hum Reprod Open, 2024, 2024(4):hoae065. doi: 10.1093/hropen/hoae065.
[5]	Pepin A, Chesnokova A, Pishko A, et al. Hormone Replacement Therapy in Patients with Gynecologic Cancer and Radiation-Induced Premature Ovarian Insufficiency[J]. Int J Radiat Oncol Biol Phys, 2025, 121(4):1042-1052. doi: 10.1016/j.ijrobp.2024. 10.023.
[6]	Yuan Z, Zhang Y, He X, et al. Engineering mesenchymal stem cells for premature ovarian failure: overcoming challenges and innovating therapeutic strategies[J]. Theranostics, 2024, 14(17):6487-6515. doi: 10.7150/thno.102641. pmid: 39479455
[7]	Fu YX, Ji J, Shan F, et al. Human mesenchymal stem cell treatment of premature ovarian failure: new challenges and opportunities[J]. Stem Cell Res Ther, 2021, 12(1):161. doi: 10.1186/s13287-021-02212-0.
[8]	Bahrehbar K, Khanjarpoor Malakhond M, Gholami S. Tracking of human embryonic stem cell-derived mesenchymal stem cells in premature ovarian failure model mice[J]. Biochem Biophys Res Commun, 2021, 577:6-11. doi: 10.1016/j.bbrc.2021.08.063.
[9]	Huang Y, Zhu M, Liu Z, et al. Bone marrow mesenchymal stem cells in premature ovarian failure: Mechanisms and prospects[J]. Front Immunol, 2022, 13:997808. doi: 10.3389/fimmu.2022. 997808.
[10]	Tian C, Ye L, Zhao X, et al. Umbilical cord mesenchymal stem cells: A novel approach to intervention of ovarian ageing[J]. Regen Ther, 2024, 26:590-598. doi: 10.1016/j.reth.2024.08.006. pmid: 39246700
[11]	Zhang M, Xie T, Dai W, et al. Umbilical Cord Mesenchymal Stem Cells Ameliorate Premature Ovarian Insufficiency in Rats[J]. Evid Based Complement Alternat Med, 2022, 2022:9228456. doi: 10.1155/2022/9228456.
[12]	Dai W, Yang H, Xu B, et al. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) alleviate excessive autophagy of ovarian granular cells through VEGFA/PI3K/AKT/mTOR pathway in premature ovarian failure rat model[J]. J Ovarian Res, 2023, 16(1):198. doi: 10.1186/s13048-023-01278-z. pmid: 37777781
[13]	He J, Ao C, Li M, et al. Clusterin-carrying extracellular vesicles derived from human umbilical cord mesenchymal stem cells restore the ovarian function of premature ovarian failure mice through activating the PI3K/AKT pathway[J]. Stem Cell Res Ther, 2024, 15(1):300. doi: 10.1186/s13287-024-03926-7. pmid: 39272156
[14]	Shen J, Wu L, Shi X, et al. Transplantation of the LRP1high subpopulation of human umbilical cord-derived mesenchymal stem cells improves ovarian function in mice with premature ovarian failure and aged mice[J]. Stem Cell Res Ther, 2024, 15(1):64. doi: 10.1186/s13287-024-03660-0.
[15]	Yang Y, Tang L, Xiao Y, et al. miR-21-5p-loaded bone mesenchymal stem cell-derived exosomes repair ovarian function in autoimmune premature ovarian insufficiency by targeting MSX1[J]. Reprod Biomed Online, 2024, 48(6):103815. doi: 10.1016/j.rbmo.2024.103815.
[16]	Ahmed AI, Dowidar MF, Negm AF, et al. Bone marrow mesenchymal stem cells expressing Neat-1, Hotair-1, miR-21, miR-644, and miR-144 subsided cyclophosphamide-induced ovarian insufficiency by remodeling the IGF-1-kisspeptin system, ovarian apoptosis, and angiogenesis[J]. J Ovarian Res, 2024, 17(1):184. doi: 10.1186/s13048-024-01498-x. pmid: 39267091
[17]	El-Derany MO, Said RS, El-Demerdash E. Bone Marrow-Derived Mesenchymal Stem Cells Reverse Radiotherapy-Induced Premature Ovarian Failure: Emphasis on Signal Integration of TGF-β, Wnt/β-Catenin and Hippo Pathways[J]. Stem Cell Rev Rep, 2021, 17(4):1429-1445. doi: 10.1007/s12015-021-10135-9. pmid: 33594662
[18]	Garg K, Zilate S. Umbilical Cord-Derived Mesenchymal Stem Cells for the Treatment of Infertility Due to Premature Ovarian Failure[J]. Cureus, 2022, 14(10):e30529. doi: 10.7759/cureus. 30529.
[19]	Zhang S, Yahaya BH, Pan Y, et al. Menstrual blood-derived endometrial stem cell, a unique and promising alternative in the stem cell-based therapy for chemotherapy-induced premature ovarian insufficiency[J]. Stem Cell Res Ther, 2023, 14(1):327. doi: 10.1186/s13287-023-03551-w. pmid: 37957675
[20]	Sadiasa A, Werkmeister JA, Gurung S, et al. Steps towards the clinical application of endometrial and menstrual fluid mesenchymal stem cells for the treatment of gynecological disorders[J]. Expert Opin Biol Ther, 2025, 25(3):285-307. doi: 10.1080/14712598.2025.2465826.
[21]	Yamchi NN, Rahbarghazi R, Bedate AM, et al. Menstrual blood CD146+ mesenchymal stem cells reduced fibrosis rate in the rat model of premature ovarian failure[J]. Cell Biochem Funct, 2021, 39(8):998-1008. doi: 10.1002/cbf.3669.
[22]	Zafardoust S, Kazemnejad S, Darzi M, et al. Intraovarian Administration of Autologous Menstrual Blood Derived-Mesenchymal Stromal Cells in Women with Premature Ovarian Failure[J]. Arch Med Res, 2023, 54(2):135-144. doi: 10.1016/j.arcmed.2022.12.015.
[23]	Li DY, Li YM, Lv DY, et al. Enhanced interaction between genome-edited mesenchymal stem cells and platelets improves wound healing in mice[J]. J Tissue Eng, 2024, 15:20417314241268917. doi: 10.1177/20417314241268917.
[24]	Almeida Galvão MG, Andrade Santos BM, Moreira Aguiar C, et al. solation, In Vitro Expansion, and Characterization of Mesenchymal Stem Cells from Mouse Epididymal Adipose Tissue[J]. J Vis Exp, 2024,203:e65722. doi: 10.3791/65722.
[25]	Ma X, Dong M, Chen B, et al. Innovative Mechanical Processing of Adipose Tissue: A Comparative Evaluation of Microfat and Concentrated Micronized Fat for Superficial Fat Grafting[J]. Aesthetic Plast Surg, 2025, 49(12):3480-3493. doi: 10.1007/s00266-024-04634-6. pmid: 39762393
[26]	Nouri N, Aghebati-Maleki L, Yousefi M. Adipose-Derived Mesenchymal Stem Cells: A Promising Tool in the Treatment of pre mature ovarian failure[J]. J Reprod Immunol, 2021, 147:103363. doi: 10.1016/j.jri.2021.103363.
[27]	Pouryousefi-Koodehi T, Shayegan S, Hashemi S, et al. Can mesenchymal stem cells derived from adipose tissue and their conditioned medium improve ovarian functions? A mini-review[J]. Zygote, 2022, 30(5):589-592. doi: 10.1017/S0967199422000235.
[28]	Un B, Cetinkaya-Un B, Akpolat M, et al. The effects of human amnion membrane-derived mesenchymal stem cells conditioned medium on ionizing radiation-induced premature ovarian failure and endoplasmic reticulum stress-related apoptosis mechanism[J]. Eur J Obstet Gynecol Reprod Biol, 2023, 288:191-197. doi: 10.1016/j.ejogrb.2023.08.001. pmid: 37566962
[29]	Gu HC, Wang LF, Zhang YW, et al. Human urine stem cells protect against cyclophosphamide-induced premature ovarian failure by inhibiting SLC1A4-mediated outflux of intracellular serine in ovarian granulosa cells[J]. Cell Mol Biol Lett, 2025, 30(1):21. doi: 10.1186/s11658-025-00701-1.
[30]	Billing AM, Dib SS, Bhagwat AM, et al. A Systems-level Characterization of the Differentiation of Human Embryonic Stem Cells into Mesenchymal Stem Cells[J]. Mol Cell Proteomics, 2019, 18(10):1950-1966. doi: 10.1074/mcp.RA119.001356. pmid: 31332097
[31]	Yimamuyushan S, Shi S, Muheremu A, et al. PEDF-Expressing mesenchymal stem cells restore ovarian function via Tim-3-Mediated immune modulation in primary ovarian failure[J]. J Ovarian Res, 2025, 18(1):182. doi: 10.1186/s13048-025-01778-0. pmid: 40814064
[32]	Tuong TVN, Duy KP, Que THC, et al. Mesenchymal stem cells and the angiogenic regulatory network with potential incorporation and modification for therapeutic development[J]. Biocell, 2024, 48(2):173-189. doi: 10.32604/BIOCELL.2023.043664.
[33]	Zhao YD, Huang YC, Li WS. Searching for the optimal precondition procedure for mesenchymal stem/stromal cell treatment: Facts and perspectives[J]. World J Stem Cells, 2024, 16(6):615-618. doi: 10.4252/wjsc.v16.i6.615.
[34]	Jalali L, Allahveisie A, Rezaei S, et al. Effect of preconditioning of human umbilical cord mesenchymal stem cells with hydrogen peroxide on the therapeutic potential of MSCs in the cyclophosphamide -induced premature ovarian failure mice model[J]. Taiwan J Obstet Gynecol, 2023, 62(5):667-676. doi: 10.1016/j.tjog.2023.07.007. pmid: 37678993
[35]	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. doi: 10.1186/s13287-022-03056-y. pmid: 35883161
[36]	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. doi: 10.1186/s13048-024-01403-6. pmid: 38622725
[37]	Li N, Fan X, Liu L, et al. Therapeutic effects of human umbilical cord mesenchymal stem cell-derived extracellular vesicles on ovarian functions through the PI3K/Akt cascade in mice with premature ovarian failure[J]. Eur J Histochem, 2023, 67(3):3506. doi: 10.4081/ejh.2023.3506.
[38]	Song Y, Wu J, Liu Y, et al. The remodeling of ovarian function: targeted delivery strategies for mesenchymal stem cells and their derived extracellular vesicles[J]. Stem Cell Res Ther, 2024, 15(1):90. doi: 10.1186/s13287-024-03704-5. pmid: 38539206
[39]	Dai F, Liu H, He J, et al. Model construction and drug therapy of primary ovarian insufficiency by ultrasound-guided injection[J]. Stem Cell Res Ther, 2024, 15(1):49. doi: 10.1186/s13287-024-03646-y. pmid: 38378684
[40]	Saharkhiz N, Hajizadeh N, Alkhafaji JS, et al. Evaluation of the therapeutic effect of very small stem cells from peripheral blood on the treatment of Premature Ovarian Failure: A pilot study[J]. JBRA Assist Reprod, 2024, 28(3):424-429. doi: 10.5935/1518-0557.20240021. pmid: 38640352
[41]	Yan L, Wu Y, Li L,etal. Clinical analysis of human umbilical cord mesenchymal stem cell allotransplantation in patients with premature ovarian insufficiency[J]. Cell Prolif, 2020, 53(12):e12938. doi: 10.1111/cpr.12938.