脐带间充质干细胞在女性生殖系统疾病治疗中应用的研究进展

doi:10.13481/j.1671-587X.20250331

摘要/Abstract

摘要：

女性生殖系统疾病，如早发性卵巢功能不全（POI）、卵巢早衰（POF）、多囊卵巢综合征（PCOS）、宫腔黏连（IUA）、子宫瘢痕憩室、输卵管炎和输卵管阻塞等可诱发不孕，严重影响患者的身心健康和生活质量。目前脐带间充质干细胞（UCMSCs）在妇产科领域的应用已成为一个新兴研究热点，在女性生殖系统疾病治疗中也展现出良好的效果。UCMSCs可分泌多种细胞因子，激活相关信号通路和关键分子，通过减少炎症介质的产生和释放，降低氧化应激的能力，阻止或延缓细胞凋亡作用，防止细胞过度损伤，从而达到治疗目的。近年来，已有大量关于UCMSCs对女性生殖系统疾病治疗效果的研究。现就UCMSCs在女性生殖系统疾病治疗的体内外研究现状及最新研究进展进行综述，旨在为未来研究和临床治疗提供新的策略及方向。

关键词: 脐带间充质干细胞, 女性生殖系统疾病, 不孕症, 组织修复与再生, 再生医学, 干细胞技术

Abstract:

Female reproductive system diseases， such as premature ovarian insufficiency （POI）， premature ovarian failure （POF）， polycystic ovary syndrome （PCOS）， intrauterine adhesions （IUA）， ulterus scar diverticulum， salpingitis， and tubal obstruction， may induce infertility， severely impacting patients’ physical and mental health and quality of life. Currently， the umbilical cord mesenchymal stem cells （UCMSCs） have emerged as a research focus in gynecological and obstetric fields， demonstrating significant therapeutic potential for female reproductive system disorders. UCMSCs secrete various cytokines， activate relevant signaling pathways and key molecules， reduce inflammation mediators and oxidative stress， and prevent excessive cellular damage and apoptosis， thereby achieving therapeutic effects. In recent years， extensive studies have explored the therapeutic effects of UCMSCs on female reproductive system diseases. This article review the current in vitro and in vivo research progress in UCMSCs for treating female reproductive system diseases， aiming to provide the novel strategies and directions for future research and clinical applications.

Key words: Umbilical cord mesenchymal stem cells, Female reproductive system diseases, Infertility, Tissue repair and regeneration, Regenerative medicine, Stem cell technology

中图分类号:

R711.7

金明明,孙然,范明慧,高璐,盛敏佳. 脐带间充质干细胞在女性生殖系统疾病治疗中应用的研究进展[J]. 吉林大学学报(医学版), 2025, 51(3): 839-847.

Mingming JIN,Ran SUN,Minghui FAN,Lu GAO,Minjia SHENG. Research progress in application of umbilical cord mesenchymal stem cells in treatment of female reproductive system diseases[J]. Journal of Jilin University(Medicine Edition), 2025, 51(3): 839-847.

参考文献 56

[1]	BARCZEWSKA M， MAKSYMOWICZ S， ZDOLIŃSKA-MALINOWSKA I， et al. Umbilical cord mesenchymal stem cells in amyotrophic lateral sclerosis： an original study［J］. Stem Cell Rev Rep， 2020， 16（5）： 922-932.
[2]	LIN T Y， CHANG T M， TSAI W C， et al. Human umbilical cord mesenchymal-stem-cell-derived extracellular vesicles reduce skin inflammation in vitro ［J］. Int J Mol Sci， 2023， 24（23）： 17109.
[3]	GUILLAMAT-PRATS R. The role of MSC in wound healing， scarring and regeneration［J］. Cells， 2021， 10（7）： 1729.
[4]	WU P P， ZHANG B， SHI H， et al. MSC-exosome： a novel cell-free therapy for cutaneous regeneration［J］. Cytotherapy， 2018， 20（3）： 291-301.
[5]	ZHAO Y X， CHEN S R， SU P P， et al. Using mesenchymal stem cells to treat female infertility： an update on female reproductive diseases［J］. Stem Cells Int， 2019， 2019： 9071720.
[6]	RIZANO A， MARGIANA R， SUPARDI S， et al. Exploring the future potential of mesenchymal stem/stromal cells and their derivatives to support assisted reproductive technology for female infertility applications［J］. Hum Cell， 2023， 36（5）： 1604-1619.
[7]	陈雨青，黄燕明. 骨髓间充质干细胞及其外泌体在女性生殖系统疾病中的应用［J］. 中国计划生育和妇产科， 2024， 16（3）： 29-32.
[8]	许发亚，何琪，李细艳，等. 人羊膜间充质干细胞在女性生殖系统的应用前景［J］. 生殖医学杂志， 2023， 32（6）： 963-967.
[9]	许思娟，倪亚莉. 月经血源性间充质干细胞在女性生殖系统疾病中的应用进展［J］. 实用妇产科杂志， 2021， 37（5）： 354-357.
[10]	MCELREAVEY K D， IRVINE A I， ENNIS K T， et al. Isolation， culture and characterisation of fibroblast-like cells derived from the Wharton’s jelly portion of human umbilical cord［J］. Biochem Soc Trans， 1991， 19（1）： 29S.
[11]	CHRISTODOULOU I， GOULIELMAKI M， KRITIKOS A， et al. Suitability of human mesenchymal stem cells derived from fetal umbilical cord （Wharton’s jelly） as an alternative in vitro model for acute drug toxicity screening［J］. Cells， 2022， 11（7）： 1102.
[12]	BAKSH D， YAO R， TUAN R S. Comparison of proliferative and multilineage differentiation potential of human mesenchymal stem cells derived from umbilical cord and bone marrow［J］. Stem Cells， 2007， 25（6）： 1384-1392.
[13]	PU L， MENG M Y， WU J， et al. Compared to the amniotic membrane， Wharton’s jelly may be a more suitable source of mesenchymal stem cells for cardiovascular tissue engineering and clinical regeneration［J］. Stem Cell Res Ther， 2017， 8（1）： 72.
[14]	CAO F J， FENG S Q. Human umbilical cord mesenchymal stem cells and the treatment of spinal cord injury［J］. Chin Med J （Engl）， 2009， 122（2）： 225-231.
[15]	MAYER H， BERTRAM H， LINDENMAIER W， et al. Vascular endothelial growth factor （VEGF-A） expression in human mesenchymal stem cells： autocrine and paracrine role on osteoblastic and endothelial differentiation［J］. J Cell Biochem， 2005， 95（4）： 827-839.
[16]	MIYOUNG L， SANG Y J， JUEUN H， et al. Low immunogenicity of allogeneic human umbilical cord blood-derived mesenchymal stem cells in vitro and in vivo ［J］. Biochem Biophys Res Commun， 2014， 446（4）： 983-989.
[17]	ZHU S J， XUAN J F， SHENTU Y C， et al. Effect of chitin-architected spatiotemporal three-dimensional culture microenvironments on human umbilical cord-derived mesenchymal stem cells［J］. Bioact Mater， 2024， 35： 291-305.
[18]	HUANG A， HUANG Y， YANG W J， et al. Fabrication of multifunctional silk nanofibril/hyaluronic acid scaffold for spinal cord repair［J］. Int J Biol Macromol， 2024， 263（Pt 1）： 130287.
[19]	HONG L M， YAN L， XIN Z M， et al. Protective effects of human umbilical cord mesenchymal stem cell-derived conditioned medium on ovarian damage［J］. J Mol Cell Biol， 2020， 12（5）： 372-385.
[20]	DAI W J， 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.
[21]	JIAO W L， MI X， YANG Y J， et al. Mesenchymal stem cells combined with autocrosslinked hyaluronic acid improve mouse ovarian function by activating the PI3K-AKT pathway in a paracrine manner［J］. Stem Cell Res Ther， 2022， 13（1）： 49.
[22]	CUI L L， BAO H C， LIU Z F， et al. hUMSCs regulate the differentiation of ovarian stromal cells via TGF-β1/Smad3 signaling pathway to inhibit ovarian fibrosis to repair ovarian function in POI rats［J］. Stem Cell Res Ther， 2020， 11（1）： 386.
[23]	ZHENG Q， FU X Y， JIANG J Z， et al. Umbilical cord mesenchymal stem cell transplantation prevents chemotherapy-induced ovarian failure via the NGF/TrkA pathway in rats［J］. Biomed Res Int， 2019， 2019： 6539294.
[24]	YIN N， WU C T， QIU J P， et al. Protective properties of heme oxygenase-1 expressed in umbilical cord mesenchymal stem cells help restore the ovarian function of premature ovarian failure mice through activating the JNK/Bcl-2 signal pathway-regulated autophagy and upregulating the circulating of CD8⁺CD28^- T cells［J］. Stem Cell Res Ther， 2020， 11（1）： 49.
[25]	LU X Y， CUI J J， CUI L L， et al. The effects of human umbilical cord-derived mesenchymal stem cell transplantation on endometrial receptivity are associated with Th1/Th2 balance change and uNK cell expression of uterine in autoimmune premature ovarian failure mice［J］. Stem Cell Res Ther， 2019， 10（1）： 214.
[26]	DENG T R， HE J， YAO Q Y， et al. Human umbilical cord mesenchymal stem cells improve ovarian function in chemotherapy-induced premature ovarian failure mice through inhibiting apoptosis and inflammation via a paracrine mechanism［J］. Reprod Sci， 2021， 28（6）： 1718-1732.
[27]	YAN L， WU Y X， LI L， et al. Clinical analysis of human umbilical cord mesenchymal stem cell allotransplantation in patients with premature ovarian insufficiency［J］. Cell Prolif， 2020， 53（12）： e12938.
[28]	DING L J， YAN G J， WANG B， et al. Transplantation of UC-MSCs on collagen scaffold activates follicles in dormant ovaries of POF patients with long history of infertility［J］. Sci China Life Sci， 2018， 61（12）： 1554-1565.
[29]	CAO M S， ZHAO Y， CHEN T， et al. Adipose mesenchymal stem cell-derived exosomal microRNAs ameliorate polycystic ovary syndrome by protecting against metabolic disturbances［J］. Biomaterials， 2022， 288： 121739.
[30]	CHUGH R M， PARK H S， ESFANDYARI S， et al. Mesenchymal stem cell-conditioned media regulate steroidogenesis and inhibit androgen secretion in a PCOS cell model via BMP-2［J］. Int J Mol Sci， 2021， 22（17）： 9184.
[31]	KALHORI Z， AZADBAKHT M， SOLEIMANI MEHRANJANI M， et al. Improvement of the folliculogenesis by transplantation of bone marrow mesenchymal stromal cells in mice with induced polycystic ovary syndrome［J］. Cytotherapy， 2018， 20（12）： 1445-1458.
[32]	XIE Q， XIONG X L， XIAO N， et al. Mesenchymal stem cells alleviate DHEA-induced polycystic ovary syndrome （PCOS） by inhibiting inflammation in mice［J］. Stem Cells Int， 2019， 2019： 9782373.
[33]	ZHAO Y Y， PAN S H， WU X H. Human umbilical cord mesenchymal stem cell-derived exosomes inhibit ovarian granulosa cells inflammatory response through inhibition of NF-κB signaling in polycystic ovary syndrome［J］. J Reprod Immunol， 2022， 152： 103638.
[34]	QIN W L， WANG J W， HU Q W， et al. Melatonin-pretreated human umbilical cord mesenchymal stem cells improved endometrium regeneration and fertility recovery through macrophage immunomodulation in rats with intrauterine adhesions［J］. Biol Reprod， 2023， 109（6）： 918-937.
[35]	ZHOU S L， LEI Y， WANG P， et al. Human umbilical cord mesenchymal stem cells encapsulated with pluronic F-127 enhance the regeneration and angiogenesis of thin endometrium in rat via local IL-1β stimulation［J］. Stem Cells Int， 2022， 2022： 7819234.
[36]	SHI Q， GAO J W， JIANG Y， et al. Differentiation of human umbilical cord Wharton’s jelly-derived mesenchymal stem cells into endometrial cells［J］. Stem Cell Res Ther， 2017， 8（1）： 246.
[37]	SUN D Y， JIANG Z H， CHEN Y L， et al. miR-455-5p upregulation in umbilical cord mesenchymal stem cells attenuates endometrial injury and promotes repair of damaged endometrium via Janus kinase/signal transducer and activator of transcription 3 signaling［J］. Bioengineered， 2021， 12（2）： 12891-12904.
[38]	LI J， HUANG B， DONG L， et al. WJ-MSCs intervention may relieve intrauterine adhesions in female rats via TGF-β1-mediated Rho/ROCK signaling inhibition［J］. Mol Med Rep， 2021， 23（1）： 8.
[39]	ZHENG Y Y， LI L H， BI X W， et al. circPTP4A2-miR-330-5p-PDK2 signaling facilitates in vivo survival of HuMSCs on SF-SIS scaffolds and improves the repair of damaged endometrium［J］. Oxid Med Cell Longev， 2022， 2022： 2818433.
[40]	ZHANG D H， DU Q Q， LI C， et al. Functionalized human umbilical cord mesenchymal stem cells and injectable HA/Gel hydrogel synergy in endometrial repair and fertility recovery［J］. Acta Biomater， 2023， 167： 205-218.
[41]	SHI Q， WANG D， DING X Y， et al. Exosome-shuttled miR-7162-3p from human umbilical cord derived mesenchymal stem cells repair endometrial stromal cell injury by restricting APOL6［J］. Arch Biochem Biophys， 2021， 707： 108887.
[42]	CAO Y， SUN H X， 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.
[43]	HUANG J R， LI Q， YUAN X H， et al. Intrauterine infusion of clinically graded human umbilical cord-derived mesenchymal stem cells for the treatment of poor healing after uterine injury： a phase I clinical trial［J］. Stem Cell Res Ther， 2022， 13（1）： 85.
[44]	CHEN Y， LI D， ZHANG Z， et al. Effect of human umbilical cord mesenchymal stem cells transplantation on nerve fibers of a rat model of endometriosis［J］. Int J Fertil Steril， 2015， 9（1）： 71-80.
[45]	TSUJI S， MUKAI T， TSUCHIYA H， et al. Impact of administering umbilical cord-derived mesenchymal stem cells to cynomolgus monkeys with endometriosis［J］. Reprod Med Biol， 2023， 22（1）： e12540.
[46]	WANG X Q， WU P L， LI X， et al. Extracellular vesicles inhibit proliferation and invasion of ovarian endometrial stromal cells and their expression of SF-1， ERβ， and aromatase［J］. Front Endocrinol （Lausanne）， 2021， 12： 666195.
[47]	FENG Y， ZHAN F L， ZHONG Y Y， et al. Effects of human umbilical cord mesenchymal stem cells derived from exosomes on migration ability of endometrial glandular epithelial cells［J］. Mol Med Rep， 2020， 22（2）： 715-722.
[48]	ZHANG F， LI F Y， LU J H. microRNA-100 shuttled by human umbilical cord MSC-secreted extracellular vesicles induces endometriosis by inhibiting HS3ST2［J］. Cell Signal， 2023， 102： 110532.
[49]	KURAMOTO G， HAMMAD I A， EINERSON B D， et al. Human mesenchymal stem cell sheets improve uterine incision repair in a rodent hysterotomy model［J］. Am J Perinatol， 2022， 39（11）： 1212-1222.
[50]	HU Q Q， XIE N， LIAO K D， et al. An injectable thermosensitive Pluronic F127/hyaluronic acid hydrogel loaded with human umbilical cord mesenchymal stem cells and asiaticoside microspheres for uterine scar repair［J］. Int J Biol Macromol， 2022， 219： 96-108.
[51]	FAN D Z， WU S Z， YE S X， et al. Umbilical cord mesenchyme stem cell local intramuscular injection for treatment of uterine niche： Protocol for a prospective， randomized， double-blinded， placebo-controlled clinical trial［J］. Medicine （Baltimore）， 2017， 96（44）： e8480.
[52]	LUO H J， XIAO X M， ZHOU J， et al. Therapeutic influence of intraperitoneal injection of Wharton’s jelly-derived mesenchymal stem cells on oviduct function and fertility in rats with acute and chronic salpingitis［J］. Genet Mol Res， 2015， 14（2）： 3606-3617.
[53]	LI Z， ZHANG Z， CHEN X， et al. Treatment evaluation of Wharton’s jelly-derived mesenchymal stem cells using a chronic salpingitis model： an animal experiment［J］. Stem Cell Res Ther， 2017， 8（1）： 232.
[54]	曹梦依，俎若雯，杨宸，等. 不同子宫内膜准备方案多囊卵巢综合征患者冻融单囊胚移植临床结局的比较［J］. 郑州大学学报（医学版）， 2024， 59（6）： 812-816.
[55]	LIAO W J， TANG X R， LI X M， et al. Therapeutic effect of human umbilical cord mesenchymal stem cells on tubal factor infertility using a chronic salpingitis murine model［J］. Arch Gynecol Obstet， 2019， 300（2）： 421-429.
[56]	ZHANG C L， LIAO W， LI W Z， et al. Human umbilical cord mesenchymal stem cells derived extracellular vesicles alleviate salpingitis by promoting M1-to-M2 transformation［J］. Front Physiol， 2023， 14： 1131701.