间充质干细胞来源外泌体在子宫内膜损伤修复中的治疗作用

doi:10.12280/gjszjk.20240565

摘要/Abstract

摘要：

各种宫腔操作均可导致子宫内膜受损，表现为宫腔粘连、子宫内膜变薄，进而导致月经量减少、闭经，甚至可能影响生育能力。目前临床上对中重度子宫内膜损伤有效的治疗方法十分有限。间充质干细胞（mesenchymal stem cell，MSC）作为一种具有多向分化潜能的干细胞，通过其分化功能和分泌外泌体功能在组织修复和再生医学领域展现出巨大的潜力。通过阐述各种来源的MSC及其外泌体对子宫内膜损伤的治疗及机制，分析其临床前景及研究方向，为临床治疗子宫内膜损伤提供新的治疗思路及方向。

关键词: 间质干细胞, 子宫内膜, 组织黏连, 外泌体, 再生医学, 治疗

Abstract:

The endometrium could be damaged during various uterine cavity operations, which manifestes as adhesions and thinning of the endometrium. Endometrial injury can lead to reduced menstrual flow, amenorrhea, and even affect fertility. At present, there are very limited effective treatments for the moderate to severe endometrial injury in clinical practice. Mesenchymal stem cells (MSCs), as a type of stem cell with multipotent differentiation potential, have shown the great potential in tissue repair and regenerative medicine through their differentiation and secretion of MSCs derived exosome. In this article, we elaborate on the treatment effects of various sources of MSCs and MSCs derived exosome on endometrial injury and the underlying mechanisms, and analyze their clinical prospects and research directions, providing new treatment ideas for the clinical treatment of endometrial injury.

Key words: Mesenchymal stem cells, Endometrium, Tissue adhesions, Exosomes, Regenerative medicine, Therapy

温碧超, 马玉珍. 间充质干细胞来源外泌体在子宫内膜损伤修复中的治疗作用[J]. 国际生殖健康/计划生育杂志, 2025, 44(3): 236-241.

WEN Bi-chao, MA Yu-zhen. Therapeutic Role of the Mesenchymal Stem Cell-Derived Exosome in Repairing Endometrial Injury[J]. Journal of International Reproductive Health/Family Planning, 2025, 44(3): 236-241.

参考文献 43

[1]	祝鑫瑜, 赵海燕, 王莉, 等. 不同负压对不全流产以及子宫内膜损伤的影响[J]. 华中科技大学学报(医学版), 2014, 43(1):106-108. doi: 10.3870/j.issn.1672-0741.2014.01.024.
[2]	Gilman AR, Dewar KM, Rhone SA, et al. Intrauterine Adhesions Following Miscarriage: Look and Learn[J]. J Obstet Gynaecol Can, 2016, 38(5):453-457. doi: 10.1016/j.jogc.2016.03.003. pmid: 27261221
[3]	Schenker JG, Margalioth EJ. Intrauterine adhesions: an updated appraisal[J]. Fertil Steril, 1982, 37(5):593-610. doi: 10.1016/s0015-0282(16)46268-0. pmid: 6281085
[4]	Gargett CE, Ye L. Endometrial reconstruction from stem cells[J]. Fertil Steril, 2012, 98(1):11-20. doi: 10.1016/j.fertnstert.2012.05.004. pmid: 22657248
[5]	Li B, Zhang Q, Sun J, et al. Human amniotic epithelial cells improve fertility in an intrauterine adhesion mouse model[J]. Stem Cell Res Ther, 2019, 10(1):257. doi: 10.1186/s13287-019-1368-9. pmid: 31412924
[6]	Gowen A, Shahjin F, Chand S, et al. Mesenchymal Stem Cell-Derived Extracellular Vesicles: Challenges in Clinical Applications[J]. Front Cell Dev Biol, 2020, 8:149. doi: 10.3389/fcell.2020.00149. pmid: 32226787
[7]	Eremichev R, Kulebyakina M, Alexandrushkina N, et al. Scar-Free Healing of Endometrium: Tissue-Specific Program of Stromal Cells and Its Induction by Soluble Factors Produced After Damage[J]. Front Cell Dev Biol, 2021, 9:616893. doi: 10.3389/fcell.2021.616893.
[8]	Spencer TE, Dunlap KA, Filant J. Comparative developmental biology of the uterus: insights into mechanisms and developmental disruption[J]. Mol Cell Endocrinol, 2012, 354(1/2):34-53. doi: 10.1016/j.mce.2011.09.035.
[9]	Spencer TE, Hayashi K, Hu J, et al. Comparative developmental biology of the mammalian uterus[J]. Curr Top Dev Biol, 2005, 68:85-122. doi: 10.1016/S0070-2153(05)68004-0. pmid: 16124997
[10]	Evans J, Salamonsen LA, Winship A, et al. Fertile ground: human endometrial programming and lessons in health and disease[J]. Nat Rev Endocrinol, 2016, 12(11):654-667. doi: 10.1038/nrendo.2016.116. pmid: 27448058
[11]	Zhang X, Goncalves R, Mosser DM. The isolation and characterization of murine macrophages[J]. Curr Protoc Immunol, 2008, Chapter 14:14.1.1-14.1.14. doi: 10.1002/0471142735.im1401s83.
[12]	Santamaria X, Mas A, Cervelló I, et al. Uterine stem cells: from basic research to advanced cell therapies[J]. Hum Reprod Update, 2018, 24(6):673-693. doi: 10.1093/humupd/dmy028. pmid: 30239705
[13]	Tempest N, Hill CJ, Maclean A, et al. Novel microarchitecture of human endometrial glands: implications in endometrial regeneration and pathologies[J]. Hum Reprod Update, 2022, 28(2):153-171. doi: 10.1093/humupd/dmab039.
[14]	Moon S, Hwang S, Kim B, et al. Hippo Signaling in the Endometrium[J]. Int J Mol Sci, 2022, 23(7):3852. doi: 10.3390/ijms23073852.
[15]	Valentijn AJ, Palial K, Al-Lamee H, et al. SSEA-1 isolates human endometrial basal glandular epithelial cells: phenotypic and functional characterization and implications in the pathogenesis of endometriosis[J]. Hum Reprod, 2013, 28(10):2695-2708. doi: 10.1093/humrep/det285.
[16]	Shaffer W. Role of uterine adhesions in the cause of multiple pregnancy losses[J]. Clin Obstet Gynecol, 1986, 29(4):912-924. doi: 10.1097/00003081-198612000-00016. pmid: 3545591
[17]	Conforti A, Alviggi C, Mollo A, et al. The management of Asherman syndrome: a review of literature[J]. Reprod Biol Endocrinol, 2013, 11:118. doi: 10.1186/1477-7827-11-118.
[18]	Deans R, Abbott J. Review of intrauterine adhesions[J]. J Minim Invasive Gynecol, 2010, 17(5):555-569. doi: 10.1016/j.jmig.2010.04.016.
[19]	Liu KE, Hartman M, Hartman A. Management of thin endometrium in assisted reproduction: a clinical practice guideline from the Canadian Fertility and Andrology Society[J]. Reprod Biomed Online, 2019, 39(1):49-62. doi: 10.1016/j.rbmo.2019.02.013. pmid: 31029557
[20]	邵小光, 魏晗, 房圣梓. 辅助生殖技术中薄型子宫内膜的诊断标准与临床处理[J]. 中国实用妇科与产科杂志, 2020, 36(6):496-500. doi: 10.19538/j.fk2020060105.
[21]	Liu F, Hu S, Wang S, et al. Cell and biomaterial-based approaches to uterus regeneration[J]. Regen Biomater, 2019, 6(3):141-148. doi: 10.1093/rb/rbz021. pmid: 31198582
[22]	Mints M, Jansson M, Sadeghi B, et al. Endometrial endothelial cells are derived from donor stem cells in a bone marrow transplant recipient[J]. Hum Reprod, 2008, 23(1):139-143. doi: 10.1093/humrep/dem342.
[23]	Cervelló I, Gil-Sanchis C, Mas A, et al. Bone marrow-derived cells from male donors do not contribute to the endometrial side population of the recipient[J]. PLoS One, 2012, 7(1):e30260. doi: 10.1371/journal.pone.0030260.
[24]	Gao L, Huang Z, Lin H, et al. Bone Marrow Mesenchymal Stem Cells (BMSCs) Restore Functional Endometrium in the Rat Model for Severe Asherman Syndrome[J]. Reprod Sci, 2019, 26(3):436-444. doi: 10.1177/1933719118799201. pmid: 30458678
[25]	Bonavina G, Mamillapalli R, Krikun G, et al. Bone marrow mesenchymal stem cell-derived exosomes shuttle microRNAs to endometrial stromal fibroblasts that promote tissue proliferation /regeneration/ and inhibit differentiation[J]. Stem Cell Res Ther, 2024, 15(1):129. doi: 10.1186/s13287-024-03716-1. pmid: 38693588
[26]	Xiao B, Zhu Y, Liu M, et al. miR-340-3p-modified bone marrow mesenchymal stem cell-derived exosomes inhibit ferroptosis through METTL3-mediated m⁶A modification of HMOX1 to promote recovery of injured rat uterus[J]. Stem Cell Res Ther, 2024, 15(1):224. doi: 10.1186/s13287-024-03846-6.
[27]	Santamaria X, Cabanillas S, Cervelló I, et al. Autologous cell therapy with CD133+ bone marrow-derived stem cells for refractory Asherman′s syndrome and endometrial atrophy: a pilot cohort study[J]. Hum Reprod, 2016, 31(5):1087-1096. doi: 10.1093/humrep/dew042.
[28]	Zhang L, Li Y, Guan CY, et al. Therapeutic effect of human umbilical cord-derived mesenchymal stem cells on injured rat endometrium during its chronic phase[J]. Stem Cell Res Ther, 2018, 9(1):36. doi: 10.1186/s13287-018-0777-5. pmid: 29433563
[29]	Zheng JH, Zhang JK, Kong DS, et al. Quantification of the CM-Dil-labeled human umbilical cord mesenchymal stem cells migrated to the dual injured uterus in SD rat[J]. Stem Cell Res Ther, 2020, 11(1):280. doi: 10.1186/s13287-020-01806-4.
[30]	Xin L, Lin X, Zhou F, et al. A scaffold laden with mesenchymal stem cell-derived exosomes for promoting endometrium regeneration and fertility restoration through macrophage immunomodulation[J]. Acta Biomater, 2020, 113:252-266. doi: 10.1016/j.actbio.2020.06.029. pmid: 32574858
[31]	Liang L, Wang L, Zhou S, et al. Exosomes derived from human umbilical cord mesenchymal stem cells repair injured endometrial epithelial cells[J]. J Assist Reprod Genet, 2020, 37(2):395-403. doi: 10.1007/s10815-019-01687-4.
[32]	Zhang S, Wang D, Yang F, et al. Intrauterine Injection of Umbilical Cord Mesenchymal Stem Cell Exosome Gel Significantly Improves the Pregnancy Rate in Thin Endometrium Rats[J]. Cell Transplant, 2022, 31:9636897221133345. doi: 10.1177/09636897221133345.
[33]	Zhang Y, Shi L, Lin X, et al. Unresponsive thin endometrium caused by Asherman syndrome treated with umbilical cord mesenchymal stem cells on collagen scaffolds: a pilot study[J]. Stem Cell Res Ther, 2021, 12(1):420. doi: 10.1186/s13287-021-02499-z. pmid: 34294152
[34]	Lv CX, Duan H, Wang S, et al. Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Promote Proliferation of Allogeneic Endometrial Stromal Cells[J]. Reprod Sci, 2020, 27(6):1372-1381. doi: 10.1007/s43032-020-00165-y.
[35]	Shao X, Ai G, Wang L, et al. Adipose-derived stem cells transplantation improves endometrial injury repair[J]. Zygote, 2019, 27(6):367-374. doi: 10.1017/S096719941900042X. pmid: 31452481
[36]	Hong J, Ahn H, Moon SY, et al. Effect of collagen endometrial patch loaded with adipose-derived mesenchymal stem cells on endometrial regeneration in rats with a thin endometrium[J]. Front Endocrinol(Lausanne), 2023, 14:1287789. doi: 10.3389/fendo.2023.1287789.
[37]	Zhao S, Qi W, Zheng J, et al. Exosomes Derived from Adipose Mesenchymal Stem Cells Restore Functional Endometrium in a Rat Model of Intrauterine Adhesions[J]. Reprod Sci, 2020, 27(6):1266-1275. doi: 10.1007/s43032-019-00112-6. pmid: 31933162
[38]	Zhao YX, Chen SR, Huang QY, et al. Repair abilities of mouse autologous adipose-derived stem cells and ShakeGel^TM 3D complex local injection with intrauterine adhesion by BMP7-Smad5 signaling pathway activation[J]. Stem Cell Res Ther, 2021, 12(1):191. doi: 10.1186/s13287-021-02258-0.
[39]	Zhu H, Pan Y, Jiang Y, et al. Activation of the Hippo/TAZ pathway is required for menstrual stem cells to suppress myofibroblast and inhibit transforming growth factor β signaling in human endometrial stromal cells[J]. Hum Reprod, 2019, 34(4):635-645. doi: 10.1093/humrep/dez001.
[40]	Tan J, Li P, Wang Q, et al. Autologous menstrual blood-derived stromal cells transplantation for severe Asherman′s syndrome[J]. Hum Reprod, 2016, 31(12):2723-2729. doi: 10.1093/humrep/dew235.
[41]	Cao Y, Sun H, Zhu H, et al. Allogeneic cell therapy using umbilical cord MSCs on collagen scaffolds for patients with recurrent uterine adhesion: a phase I clinical trial[J]. Stem Cell Res Ther, 2018, 9(1):192. doi: 10.1186/s13287-018-0904-3. pmid: 29996892
[42]	姜小花. 水凝胶微胶囊化间充质干细胞及其来源的外泌体对宫腔粘连的作用及机制研究[D]. 合肥: 安徽医科大学, 2023.
[43]	Prakash R, Mishra RK, Ahmad A, et al. Sivelestat-loaded nanostructured lipid carriers modulate oxidative and inflammatory stress in human dental pulp and mesenchymal stem cells subjected to oxygen-glucose deprivation[J]. Mater Sci Eng C Mater Biol Appl, 2021, 120:111700. doi: 10.1016/j.msec.2020.111700.