https://doi.org/10.4081/ejh.2023.3506

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

Vol. 67 No. 3 (2023)
Submitted: 28 July 2022
Accepted: 28 December 2022
Published: 27 July 2023
Premature ovarian failure, human umbilical cord mesenchymal stem cells, extracellular vesicles, PI3K/Akt, therapeutic effects, D-galactose
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Authors

Nan Li
Department of Gynecological Ward, The Third Affiliated Hospital, Jinzhou Medical University, Jinzhou, China.
Xue Fan
XueFan0520@163.com
Department of Gynecological Ward, The Third Affiliated Hospital, Jinzhou Medical University, Jinzhou, China.
Lihong Liu
Department of Gynecological Ward, The Third Affiliated Hospital, Jinzhou Medical University, Jinzhou, China.
Yanbing Liu
Department of Gynecological Ward, The Third Affiliated Hospital, Jinzhou Medical University, Jinzhou, China.

Premature ovarian failure (POF) mainly refers to ovarian dysfunction in females younger than forty. Mesenchymal stem cells (MSCs) are considered an increasingly promising therapy for POF. This study intended to uncover the therapeutic effects of human umbilical cord MSC-derived extracellular vesicles (hucMSCEVs) on POF. hucMSCs were identified by observing morphology and examining differentiation capabilities. EVs were extracted from hucMSCs and later identified utilizing nanoparticle tracking analysis, transmission electron microscopy, and Western blotting. POF mouse models were established by injecting D-galactose (Dgal). The estrous cycles were assessed through vaginal cytology, and serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-mullerian hormone (AMH), estradiol (E2), and progesterone (P) were measured by ELISA. The human ovarian granulosa cell line KGN was used for in vitro experiments. The uptake of hucMSC-EVs by KGN cells was detected. After D-gal treatment, cell proliferation and apoptosis were assessed via CCK-8 assay and flow cytometry. The PI3K/Akt pathway-related proteins were determined by Western blotting. Our results revealed that POF mice had prolonged estrous cycles, increased FSH and LH levels, and decreased AMH, E2, and P levels. Treatment with hucMSC-EVs partially counteracted the above changes. D-gal treatment reduced proliferation and raised apoptosis in KGN cells, while hucMSC-EV treatment annulled the changes. D-gal-treated cells exhibited downregulated p-PI3K/PI3K and p-Akt/Akt levels, while hucMSC-EVs activated the PI3K/Akt pathway. LY294002 suppressed the roles of hucMSC-EVs in promoting KGN cell proliferation and lowering apoptosis. Collectively, hucMSC-EVs facilitate proliferation and suppress apoptosis of ovarian granulosa cells by activating the PI3K/Akt pathway, thereby alleviating POF.

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Scopus
Google Scholar
Europe PMC
Goswami D, Conway GS. Premature ovarian failure. Hum Reprod Update 2005;11:391-410. DOI: https://doi.org/10.1093/humupd/dmi012
Sassarini J, Lumsden MA, Critchley HO. Sex hormone replacement in ovarian failure - new treatment concepts. Best Pract Res Clin Endocrinol Metab 2015;29:105-14. DOI: https://doi.org/10.1016/j.beem.2014.09.010
Pierce SB, Gersak K, Michaelson-Cohen R, Walsh T, Lee MK, Malach D, et al. Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome. Am J Hum Genet 2013;92:614-20. DOI: https://doi.org/10.1016/j.ajhg.2013.03.007
Wang MY, Wang YX, Li-Ling J, Xie HQ. Adult stem cell therapy for premature ovarian failure: from bench to bedside. Tissue Eng Part B Rev 2022;28:63-78. DOI: https://doi.org/10.1089/ten.teb.2020.0205
European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI, Webber L, Davies M, Anderson R, Bartlett J, et al. ESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod 2016;31:926-37. DOI: https://doi.org/10.1093/humrep/dew027
Ghahremani-Nasab M, Ghanbari E, Jahanbani Y, Mehdizadeh A, Yousefi M. Premature ovarian failure and tissue engineering. J Cell Physiol 2020;235:4217-26. DOI: https://doi.org/10.1002/jcp.29376
Leidal AM, Debnath J. Unraveling the mechanisms that specify molecules for secretion in extracellular vesicles. Methods 2020;177:15-26. DOI: https://doi.org/10.1016/j.ymeth.2020.01.008
Sil S, Dagur RS, Liao K, Peeples ES, Hu G, Periyasamy P, et al. Strategies for the use of extracellular vesicles for the delivery of therapeutics. J Neuroimmune Pharmacol 2020;15:422-42. DOI: https://doi.org/10.1007/s11481-019-09873-y
Thakur A, Ke X, Chen YW, Motallebnejad P, Zhang K, Lian Q, et al. The mini player with diverse functions: extracellular vesicles in cell biology, disease, and therapeutics. Protein Cell 2022;13:631-54. DOI: https://doi.org/10.1007/s13238-021-00863-6
Gao J, Dong X, Wang Z. Generation, purification and engineering of extracellular vesicles and their biomedical applications. Methods 2020;177:114-25. DOI: https://doi.org/10.1016/j.ymeth.2019.11.012
Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 2013;200:373-83. DOI: https://doi.org/10.1083/jcb.201211138
Regmi S, Pathak S, Kim JO, Yong CS, Jeong JH. Mesenchymal stem cell therapy for the treatment of inflammatory diseases: Challenges, opportunities, and future perspectives. Eur J Cell Biol 2019;98:151041. DOI: https://doi.org/10.1016/j.ejcb.2019.04.002
Zhang C. The roles of different stem cells in premature ovarian failure. Curr Stem Cell Res Ther 2020;15:473-81. DOI: https://doi.org/10.2174/1574888X14666190314123006
Abbaszadeh H, Ghorbani F, Derakhshani M, Movassaghpour A, Yousefi M. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles: A novel therapeutic paradigm. J Cell Physiol 2020;235:706-17. DOI: https://doi.org/10.1002/jcp.29004
Grosbois J, Demeestere I. Dynamics of PI3K and Hippo signaling pathways during in vitro human follicle activation. Hum Reprod 2018;33:1705-14. DOI: https://doi.org/10.1093/humrep/dey250
Kawamura K, Kawamura N, Hsueh AJ. Activation of dormant follicles: a new treatment for premature ovarian failure? Curr Opin Obstet Gynecol 2016;28:217-22. DOI: https://doi.org/10.1097/GCO.0000000000000268
Han Y, Yao R, Yang Z, Li S, Meng W, Zhang Y, et al. Interleukin-4 activates the PI3K/AKT signaling to promote apoptosis and inhibit the proliferation of granulosa cells. Exp Cell Res 2022;412:113002. DOI: https://doi.org/10.1016/j.yexcr.2021.113002
Liang QX, Wang ZB, Lin F, Zhang CH, Sun HM, Zhou L, et al. Ablation of beta subunit of protein kinase CK2 in mouse oocytes causes follicle atresia and premature ovarian failure. Cell Death Dis 2018;9:508. DOI: https://doi.org/10.1038/s41419-018-0505-1
Nam EY, Kim SA, Kim H, Kim SH, Han JH, Lee JH, et al. Akt activation by Evodiae fructus extract protects ovary against 4-vinylcyclohexene diepoxide-induced ovotoxicity. J Ethnopharmacol 2016;194:733-9. DOI: https://doi.org/10.1016/j.jep.2016.10.048
Simm A, Casselmann C, Schubert A, Hofmann S, Reimann A, Silber RE. Age associated changes of AGE-receptor expression: RAGE upregulation is associated with human heart dysfunction. Exp Gerontol 2004;39:407-13. DOI: https://doi.org/10.1016/j.exger.2003.12.006
Schinzel R, Munch G, Heidland A, Sebekova K. Advanced glycation end products in end-stage renal disease and their removal. Nephron 2001;87:295-303. DOI: https://doi.org/10.1159/000045934
Nerlich AG, Schleicher ED. N(epsilon)-(carboxymethyl)lysine in atherosclerotic vascular lesions as a marker for local oxidative stress. Atherosclerosis 1999;144:41-7. DOI: https://doi.org/10.1016/S0021-9150(99)00038-6
Kimura T, Takamatsu J, Ikeda K, Kondo A, Miyakawa T, Horiuchi S. Accumulation of advanced glycation end products of the Maillard reaction with age in human hippocampal neurons. Neurosci Lett 1996;208:53-6. DOI: https://doi.org/10.1016/0304-3940(96)12537-4
Hyogo H, Yamagishi S. Advanced glycation end products (AGEs) and their involvement in liver disease. Curr Pharm Des 2008;14:969-72. DOI: https://doi.org/10.2174/138161208784139701
Haus JM, Carrithers JA, Trappe SW, Trappe TA. Collagen, cross-linking, and advanced glycation end products in aging human skeletal muscle. J Appl Physiol (1985) 2007;103:2068-76. DOI: https://doi.org/10.1152/japplphysiol.00670.2007
Bandyopadhyay S, Chakrabarti J, Banerjee S, Pal AK, Goswami SK, Chakravarty BN, et al. Galactose toxicity in the rat as a model for premature ovarian failure: an experimental approach readdressed. Hum Reprod 2003;18:2031-8. DOI: https://doi.org/10.1093/humrep/deg414
Liang X, Yan Z, Ma W, Qian Y, Zou X, Cui Y, et al. Peroxiredoxin 4 protects against ovarian ageing by ameliorating D-galactose-induced oxidative damage in mice. Cell Death Dis 2020;11:1053. DOI: https://doi.org/10.1038/s41419-020-03253-8
Wang L, Gu Z, Zhao X, Yang N, Wang F, Deng A, et al. Extracellular vesicles released from human umbilical cord-derived mesenchymal stromal cells prevent life-threatening acute graft-versus-host disease in a mouse model of allogeneic hematopoietic stem cell transplantation. Stem Cells Dev 2016;25:1874-83. DOI: https://doi.org/10.1089/scd.2016.0107
Brill A, Dashevsky O, Rivo J, Gozal Y, Varon D. Platelet-derived microparticles induce angiogenesis and stimulate post-ischemic revascularization. Cardiovasc Res 2005;67:30-8. DOI: https://doi.org/10.1016/j.cardiores.2005.04.007
Collino F, Deregibus MC, Bruno S, Sterpone L, Aghemo G, Viltono L, et al. Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS One 2010;5:e11803. DOI: https://doi.org/10.1371/journal.pone.0011803
Wang G, Xie L, Li B, Sang W, Yan J, Li J, et al. A nanounit strategy reverses immune suppression of exosomal PD-L1 and is associated with enhanced ferroptosis. Nat Commun 2021;12:5733. DOI: https://doi.org/10.1038/s41467-021-25990-w
Luberto C, Hassler DF, Signorelli P, Okamoto Y, Sawai H, Boros E, et al. Inhibition of tumor necrosis factor-induced cell death in MCF7 by a novel inhibitor of neutral sphingomyelinase. J Biol Chem 2002;277:41128-39. DOI: https://doi.org/10.1074/jbc.M206747200
Song X, Bao M, Li D, Li YM. Advanced glycation in D-galactose induced mouse aging model. Mech Ageing Dev 1999;108:239-51. DOI: https://doi.org/10.1016/S0047-6374(99)00022-6
Semba RD, Nicklett EJ, Ferrucci L. Does accumulation of advanced glycation end products contribute to the aging phenotype? J Gerontol A Biol Sci Med Sci 2010;65:963-75. DOI: https://doi.org/10.1093/gerona/glq074
Banerjee S, Chakraborty P, Saha P, Bandyopadhyay SA, Banerjee S, Kabir SN. Ovotoxic effects of galactose involve attenuation of follicle-stimulating hormone bioactivity and up-regulation of granulosa cell p53 expression. PLoS One 2012;7:e30709. DOI: https://doi.org/10.1371/journal.pone.0030709
Liu M, Qiu Y, Xue Z, Wu R, Li J, Niu X, et al. Small extracellular vesicles derived from embryonic stem cells restore ovarian function of premature ovarian failure through PI3K/AKT signaling pathway. Stem Cell Res Ther 2020;11:3. DOI: https://doi.org/10.1186/s13287-019-1508-2
Ding C, Zou Q, Wu Y, Lu J, Qian C, Li H, et al. EGF released from human placental mesenchymal stem cells improves premature ovarian insufficiency via NRF2/HO-1 activation. Aging (Albany NY) 2020;12:2992-3009. DOI: https://doi.org/10.18632/aging.102794
Yao J, Ma Y, Zhou S, Bao T, Mi Y, Zeng W, et al. Metformin prevents follicular atresia in aging laying chickens through activation of PI3K/AKT and calcium signaling pathways. Oxid Med Cell Longev 2020;2020:3648040. DOI: https://doi.org/10.1155/2020/3648040
Dragojevic-Dikic S, Marisavljevic D, Mitrovic A, Dikic S, Jovanovic T, Jankovic-Raznatovic S. An immunological insight into premature ovarian failure (POF). Autoimmun Re. 2010;9:771-4. DOI: https://doi.org/10.1016/j.autrev.2010.06.008
Witwer KW, Buzas EI, Bemis LT, Bora A, Lasser C, Lotvall J, et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles 2013;2:20360. DOI: https://doi.org/10.3402/jev.v2i0.20360
Liao Z, Liu C, Wang L, Sui C, Zhang H. Therapeutic role of mesenchymal stem cell-derived extracellular vesicles in female reproductive diseases. Front Endocrinol (Lausanne) 2021;12:665645. DOI: https://doi.org/10.3389/fendo.2021.665645
Rezaie J, Nejati V, Mahmoodi M, Ahmadi M. Mesenchymal stem cells derived extracellular vesicles: A promising nanomedicine for drug delivery system. Biochem Pharmacol 2022;203:115167. DOI: https://doi.org/10.1016/j.bcp.2022.115167
Sun B, Ma Y, Wang F, Hu L, Sun Y. miR-644-5p carried by bone mesenchymal stem cell-derived exosomes targets regulation of p53 to inhibit ovarian granulosa cell apoptosis. Stem Cell Res Ther 2019;10:360. DOI: https://doi.org/10.1186/s13287-019-1442-3
Li Z, Zhang M, Zheng J, Tian Y, Zhang H, Tan Y, 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. Front Endocrinol (Lausanne) 2021;12:711902. DOI: https://doi.org/10.3389/fendo.2021.711902
Ding C, Zhu L, Shen H, Lu J, Zou Q, Huang C, et al. Exosomal miRNA-17-5p derived from human umbilical cord mesenchymal stem cells improves ovarian function in premature ovarian insufficiency by regulating SIRT7. Stem Cells 2020;38:1137-48. DOI: https://doi.org/10.1002/stem.3204
Fan D, Wu S, Ye S, Wang W, Guo X, Liu Z. Umbilical cord mesenchyme stem cell local intramuscular injection for treatment of uterine niche: Protocol for a prospective, randomized, double-blinded, placebo-controlled clinical trial. Medicine (Baltimore) 2017;96:e8480. DOI: https://doi.org/10.1097/MD.0000000000008480
Yan Z, Dai Y, Fu H, Zheng Y, Bao D, Yin Y, et al. Curcumin exerts a protective effect against premature ovarian failure in mice. J Mol Endocrinol 2018;60:261-71. DOI: https://doi.org/10.1530/JME-17-0214
He L, Ling L, Wei T, Wang Y, Xiong Z. Ginsenoside Rg1 improves fertility and reduces ovarian pathological damages in premature ovarian failure model of mice. Exp Biol Med (Maywood) 2017;242:683-91. DOI: https://doi.org/10.1177/1535370217693323
Cordts EB, Christofolini DM, Dos Santos AA, Bianco B, Barbosa CP. Genetic aspects of premature ovarian failure: a literature review. Arch Gynecol Obstet 2011;283:635-43. DOI: https://doi.org/10.1007/s00404-010-1815-4
Sha C, Chen L, Lin L, Li T, Wei H, Yang M, et al. TRDMT1 participates in the DNA damage repair of granulosa cells in premature ovarian failure. Aging (Albany NY) 2021;13:15193-213. DOI: https://doi.org/10.18632/aging.203080
Shamseddine AA, Airola MV, Hannun YA. Roles and regulation of neutral sphingomyelinase-2 in cellular and pathological processes. Adv Biol Regul 2015;57:24-41. DOI: https://doi.org/10.1016/j.jbior.2014.10.002
Catalano M, O'Driscoll L. Inhibiting extracellular vesicles formation and release: a review of EV inhibitors. J Extracell Vesicles 2020;9:1703244. DOI: https://doi.org/10.1080/20013078.2019.1703244
Zhou H, Shen X, Yan C, Xiong W, Ma Z, Tan Z, et al. Extracellular vesicles derived from human umbilical cord mesenchymal stem cells alleviate osteoarthritis of the knee in mice model by interacting with METTL3 to reduce m6A of NLRP3 in macrophage. Stem Cell Res Ther 2022;13:322. DOI: https://doi.org/10.1186/s13287-022-03005-9
Yin S, Ji C, Wu P, Jin C, Qian H. Human umbilical cord mesenchymal stem cells and exosomes: bioactive ways of tissue injury repair. Am J Transl Res 2019;11:1230-40.
Zhu Z, Zhang Y, Zhang Y, Zhang H, Liu W, Zhang N, et al. Exosomes derived from human umbilical cord mesenchymal stem cells accelerate growth of VK2 vaginal epithelial cells through MicroRNAs in vitro. Hum Reprod 2019;34:248-60. DOI: https://doi.org/10.1093/humrep/dey344
Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007;9:654-9. DOI: https://doi.org/10.1038/ncb1596
Sun G, Li G, Li D, Huang W, Zhang R, Zhang H, et al. hucMSC derived exosomes promote functional recovery in spinal cord injury mice via attenuating inflammation. Mater Sci Eng C Mater Biol Appl 2018;89:194-204. DOI: https://doi.org/10.1016/j.msec.2018.04.006
Gao T, Cao Y, Hu M, Du Y. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles carrying MicroRNA-29a improves ovarian function of mice with primary ovarian insufficiency by targeting HMG-Box transcription factor/Wnt/beta-catenin signaling. Dis Markers 2022;2022:5045873. DOI: https://doi.org/10.1155/2022/5045873
Yang Y, Lei L, Wang S, Sheng X, Yan G, Xu L, et al. Transplantation of umbilical cord-derived mesenchymal stem cells on a collagen scaffold improves ovarian function in a premature ovarian failure model of mice. In Vitro Cell Dev Biol Anim 2019;55:302-11. DOI: https://doi.org/10.1007/s11626-019-00337-4
Zhang X, Zhang L, Li Y, Yin Z, Feng Y, Ji Y. Human umbilical cord mesenchymal stem cells (hUCMSCs) promotes the recovery of ovarian function in a rat model of premature ovarian failure (POF). Gynecol Endocrinol 2021;37:353-7. DOI: https://doi.org/10.1080/09513590.2021.1878133
Tu J, Cheung AH, Chan CL, Chan WY. The role of microRNAs in ovarian granulosa cells in health and disease. Front Endocrinol (Lausanne) 2019;10:174. DOI: https://doi.org/10.3389/fendo.2019.00174
Yu Y, Zhang Q, Sun K, Xiu Y, Wang X, Wang K, et al. Long non-coding RNA BBOX1 antisense RNA 1 increases the apoptosis of granulosa cells in premature ovarian failure by sponging miR-146b. Bioengineered 2022;13:6092-9. DOI: https://doi.org/10.1080/21655979.2022.2031675
Sun YT, Cai JH, Bao S. Overexpression of lncRNA HCP5 in human umbilical cord mesenchymal stem cell-derived exosomes promoted the proliferation and inhibited the apoptosis of ovarian granulosa cells via the musashi RNA-binding protein 2/oestrogen receptor alpha 1 axis. Endocr J 2022;69:1117-29. DOI: https://doi.org/10.1507/endocrj.EJ21-0653
Wang S, Lin S, Zhu M, Li C, Chen S, Pu L, et al. Acupuncture reduces apoptosis of granulosa cells in rats with premature ovarian failure via restoring the PI3K/Akt signaling pathway. Int J Mol Sci 2019;20:6311. DOI: https://doi.org/10.3390/ijms20246311
Li N, Liu L. Mechanism of resveratrol in improving ovarian function in a rat model of premature ovarian insufficiency. J Obstet Gynaecol Res 2018;44:1431-8. DOI: https://doi.org/10.1111/jog.13680
Yang Z, Du X, Wang C, Zhang J, Liu C, Li Y, et al. Therapeutic effects of human umbilical cord mesenchymal stem cell-derived microvesicles on premature ovarian insufficiency in mice. Stem Cell Res Ther 2019;10:250. DOI: https://doi.org/10.1186/s13287-019-1327-5
Vo KCT, Kawamura K. In vitro activation early follicles: from the basic science to the clinical perspectives. Int J Mol Sci 2021;22:3785. DOI: https://doi.org/10.3390/ijms22073785
Laronda MM, Jakus AE, Whelan KA, Wertheim JA, Shah RN, Woodruff TK. Initiation of puberty in mice following decellularized ovary transplant. Biomaterials 2015;50:20-9. DOI: https://doi.org/10.1016/j.biomaterials.2015.01.051
Kniazeva E, Hardy AN, Boukaidi SA, Woodruff TK, Jeruss JS, Shea LD. Primordial follicle transplantation within designer biomaterial grafts produce live births in a mouse infertility model. Sci Rep 2015;5:17709. DOI: https://doi.org/10.1038/srep17709
Chen J, Torres-de la Roche LA, Kahlert UD, Isachenko V, Huang H, Hennefrund J, et al. Artificial ovary for young female breast cancer patients. Front Med (Lausanne) 2022;9:837022. DOI: https://doi.org/10.3389/fmed.2022.837022

Ethics Approval

Animal experiments were ratified by the Ethics Committee of The Third Affiliated Hospital, Jinzhou Medical University (JZ2021023)

How to Cite

Li, N., Fan, X., Liu, L., & Liu, Y. (2023). 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. European Journal of Histochemistry, 67(3). https://doi.org/10.4081/ejh.2023.3506
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