4.6

CiteScore

2.2

Impact Factor
  • ISSN 1674-8301
  • CN 32-1810/R
Wenjing Tang, Haiyan Yan, Xiaojun Chen, Yanan Pu, Xin Qi, Liyang Dong, Chuan Su. hUCMSC-derived extracellular vesicles relieve cisplatin-induced granulosa cell apoptosis in mice by transferring anti-apoptotic miRNAs[J]. The Journal of Biomedical Research, 2025, 39(1): 36-49. DOI: 10.7555/JBR.37.20230310
Citation: Wenjing Tang, Haiyan Yan, Xiaojun Chen, Yanan Pu, Xin Qi, Liyang Dong, Chuan Su. hUCMSC-derived extracellular vesicles relieve cisplatin-induced granulosa cell apoptosis in mice by transferring anti-apoptotic miRNAs[J]. The Journal of Biomedical Research, 2025, 39(1): 36-49. DOI: 10.7555/JBR.37.20230310

hUCMSC-derived extracellular vesicles relieve cisplatin-induced granulosa cell apoptosis in mice by transferring anti-apoptotic miRNAs

More Information
  • Corresponding author:

    Chuan Su, State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Pathogen Biology & Immunology, Nanjing Medical University, 101 Longmian Road, Nanjing, Jiangsu 211166, China. E-mail: chuan_su@126.com

  • Received Date: December 17, 2023
  • Revised Date: April 15, 2024
  • Accepted Date: April 21, 2024
  • Available Online: April 22, 2024
  • Published Date: May 28, 2024
  • Premature ovarian insufficiency (POI) caused by chemotherapy is a common complication in female cancer survivors of childbearing age. Traditional methods, including mesenchymal stem cell (MSC) transplant and hormone replacement therapy, have limited clinical application because of their drawbacks, and more methods need to be developed. In the current study, the potential effects and underlying mechanisms of human umbilical cord MSC-derived extracellular vesicles (hUCMSC-EVs) were investigated in a cisplatin (CDDP)-induced POI mouse model and a human granulosa cell (GC) line. The results showed that hUCMSC-EVs significantly attenuated body weight loss, ovarian weight loss, ovary atrophy, and follicle loss in moderate-dose (1.5 mg/kg) CDDP-induced POI mice, similar to the effects observed with hUCMSCs. We further found that the hUCMSC-EVs inhibited CDDP-induced ovarian GC apoptosis by upregulating anti-apoptotic miRNA levels in GCs, thereby downregulating the mRNA levels of multiple pro-apoptotic genes. In general, our findings indicate that the moderate-dose chemotherapy may be a better choice for clinical oncotherapy, considering effective rescue of the oncotherapy-induced ovarian damage with hUCMSC-EVs. Additionally, multiple miRNAs in hUCMSC-EVs may potentially be used to inhibit the chemotherapy-induced ovarian GC apoptosis, thereby restoring ovarian function and improving the life quality of female cancer patients.

  • We thank Professor Li Jing from State Key Laboratory of Reproductive Medicine and Offspring Health for offering us biological materials in this research. We thank Jinyang Cai from the State Key Laboratory of Reproductive Medicine and Offspring Health for assistance in microscopy.

    Financial support for the current study was provided by the grant from "Blue Engineering" Excellent Young Teacher Foundation in Colleges and Universities of Jiangsu Province (Grant No. KY101R202207 to Xiaojun Chen).

    CLC number: R711.75; R730.53, Document code: A

    The authors reported no conflict of interests.

  • [1]
    Rebar RW, Keator CS. Expanding our knowledge of premature ovarian insufficiency[J]. Fertil Steril, 2021, 115(2): 328–329. doi: 10.1016/j.fertnstert.2020.09.145
    [2]
    Armeni E, Paschou SA, Goulis DG, et al. Hormone therapy regimens for managing the menopause and premature ovarian insufficiency[J]. Best Pract Res Clin Endocrinol Metab, 2021, 35(6): 101561. doi: 10.1016/j.beem.2021.101561
    [3]
    Rossetti R, Ferrari I, Bonomi M, et al. Genetics of primary ovarian insufficiency[J]. Clin Genet, 2017, 91(2): 183–198. doi: 10.1111/cge.12921
    [4]
    Zhang S, Zhu D, Mei X, et al. Advances in biomaterials and regenerative medicine for primary ovarian insufficiency therapy[J]. Bioact Mater, 2021, 6(7): 1957–1972. doi: 10.1016/j.bioactmat.2020.12.008
    [5]
    Gargus E, Deans R, Anazodo A, et al. Management of primary ovarian insufficiency symptoms in survivors of childhood and adolescent cancer[J]. J Natl Compr Canc Netw, 2018, 16(9): 1137–1149. doi: 10.6004/jnccn.2018.7023
    [6]
    Romani AMP. Cisplatin in cancer treatment[J]. Biochem Pharmacol, 2022, 206: 115323. doi: 10.1016/j.bcp.2022.115323
    [7]
    Liu C, Pan B, Yang L, et al. Beta defensin 3 enhances ovarian granulosa cell proliferation and migration via ERK1/2 pathway in vitro[J]. Biol Reprod, 2019, 100(4): 1057–1065. doi: 10.1093/biolre/ioy246
    [8]
    Wang Q, Li X, Wang Q, et al. Heat shock pretreatment improves mesenchymal stem cell viability by heat shock proteins and autophagy to prevent cisplatin-induced granulosa cell apoptosis[J]. Stem Cell Res Ther, 2019, 10(1): 348. doi: 10.1186/s13287-019-1425-4
    [9]
    Mikhael S, Punjala-Patel A, Gavrilova-Jordan L. Hypothalamic-pituitary-ovarian axis disorders impacting female fertility[J]. Biomedicines, 2019, 7(1): 5. doi: 10.3390/biomedicines7010005
    [10]
    Matsuda F, Inoue N, Manabe N, et al. Follicular growth and atresia in mammalian ovaries: regulation by survival and death of granulosa cells[J]. J Reprod Dev, 2012, 58(1): 44–50. doi: 10.1262/jrd.2011-012
    [11]
    Yamanaka S. Pluripotent stem cell-based cell therapy-promise and challenges[J]. Cell Stem Cell, 2020, 27(4): 523–531. doi: 10.1016/j.stem.2020.09.014
    [12]
    Xie Q, Liu R, Jiang J, et al. What is the impact of human umbilical cord mesenchymal stem cell transplantation on clinical treatment?[J]. Stem Cell Res Ther, 2020, 11(1): 519. doi: 10.1186/s13287-020-02011-z
    [13]
    Lelek J, Zuba-Surma EK. Perspectives for future use of extracellular vesicles from umbilical cord- and adipose tissue-derived mesenchymal stem/stromal cells in regenerative therapies-synthetic review[J]. Int J Mol Sci, 2020, 21(3): 799. doi: 10.3390/ijms21030799
    [14]
    Kotani A, Ito M, Kudo K. Non-coding RNAs and lipids mediate the function of extracellular vesicles in cancer cross-talk[J]. Semin Cancer Biol, 2021, 74: 121–133. doi: 10.1016/j.semcancer.2021.04.017
    [15]
    Polonio AM, García-Velasco JA, Herraiz S. Stem cell paracrine signaling for treatment of premature ovarian insufficiency[J]. Front Endocrinol, 2021, 11: 626322. doi: 10.3389/fendo.2020.626322
    [16]
    Pan R, Ryan J, Pan D, et al. Augmenting NK cell-based immunotherapy by targeting mitochondrial apoptosis[J]. Cell, 2022, 185(9): 1521–1538.e18. doi: 10.1016/j.cell.2022.03.030
    [17]
    Hoang DM, Pham PT, Bach TQ, et al. Stem cell-based therapy for human diseases[J]. Signal Transduct Target Ther, 2022, 7(1): 272. doi: 10.1038/s41392-022-01134-4
    [18]
    Dong L, Pu Y, Zhang L, et al. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles promote lung adenocarcinoma growth by transferring miR-410[J]. Cell Death Dis, 2018, 9(2): 218. doi: 10.1038/s41419-018-0323-5
    [19]
    Wang Z, Wang Y, Yang T, et al. Study of the reparative effects of menstrual-derived stem cells on premature ovarian failure in mice[J]. Stem Cell Res Ther, 2017, 8(1): 11. doi: 10.1186/s13287-016-0458-1
    [20]
    Chen W, Xu X, Wang L, et al. Low expression of Mfn2 is associated with mitochondrial damage and apoptosis of ovarian tissues in the premature ovarian failure model[J]. PLoS One, 2015, 10(9): e0136421. doi: 10.1371/journal.pone.0136421
    [21]
    Gouy S, Ferron G, Glehen O, et al. Results of a multicenter phase I dose-finding trial of hyperthermic intraperitoneal cisplatin after neoadjuvant chemotherapy and complete cytoreductive surgery and followed by maintenance bevacizumab in initially unresectable ovarian cancer[J]. Gynecol Oncol, 2016, 142(2): 237–242. doi: 10.1016/j.ygyno.2016.05.032
    [22]
    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
    [23]
    O'Brien K, Breyne K, Ughetto S, et al. RNA delivery by extracellular vesicles in mammalian cells and its applications[J]. Nat Rev Mol Cell Biol, 2020, 21(10): 585–606. doi: 10.1038/s41580-020-0251-y
    [24]
    Zhang Z, Zou X, Zhang R, et al. Human umbilical cord mesenchymal stem cell-derived exosomal miR-146a-5p reduces microglial-mediated neuroinflammation via suppression of the IRAK1/TRAF6 signaling pathway after ischemic stroke[J]. Aging (Albany NY), 2021, 13(2): 3060–3079. doi: 10.18632/aging.202466
    [25]
    Zhu Z, Zhang Y, Zhang Y, et al. Exosomes derived from human umbilical cord mesenchymal stem cells accelerate growth of VK2 vaginal epithelial cells through MicroRNAs in vitro[J]. Hum Reprod, 2019, 34(2): 248–260. doi: 10.1093/humrep/dey344
    [26]
    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): 1137–1148. doi: 10.1002/stem.3204
    [27]
    Cao J, Wang B, Tang T, et al. Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury[J]. Theranostics, 2021, 11(11): 5248–5266. doi: 10.7150/thno.54550
    [28]
    Wang Y, Lai X, Wu D, et al. Umbilical mesenchymal stem cell-derived exosomes facilitate spinal cord functional recovery through the miR-199a-3p/145-5p-mediated NGF/TrkA signaling pathway in rats[J]. Stem Cell Res Ther, 2021, 12(1): 117. doi: 10.1186/s13287-021-02148-5
    [29]
    Fabian MR, Sonenberg N, Filipowicz W. Regulation of mRNA translation and stability by microRNAs[J]. Annu Rev Biochem, 2010, 79: 351–379. doi: 10.1146/annurev-biochem-060308-103103
    [30]
    Sullivan SD, Sarrel PM, Nelson LM. Hormone replacement therapy in young women with primary ovarian insufficiency and early menopause[J]. Fertil Steril, 2016, 106(7): 1588–1599. doi: 10.1016/j.fertnstert.2016.09.046
    [31]
    Bayefsky MJ, Sampson A, Blakemore JK, et al. Experiences and intentions of patients undergoing medically indicated oocyte or embryo cryopreservation: a qualitative study[J]. Hum Reprod, 2024, 39(1): 147–153. doi: 10.1093/humrep/dead228
    [32]
    Tsang RY, Al-Fayea T, Au HJ. Cisplatin overdose: toxicities and management[J]. Drug Saf, 2009, 32(12): 1109–1122. doi: 10.2165/11316640-000000000-00000
    [33]
    Meng X, Ma F, Yu D. The diverse effects of cisplatin on tumor microenvironment: insights and challenges for the delivery of cisplatin by nanoparticles[J]. Environ Res, 2024, 240(Pt 1): 117362.
    [34]
    Federico C, Sun J, Muz B, et al. Localized delivery of cisplatin to cervical cancer improves its therapeutic efficacy and minimizes its side effect profile[J]. Int J Radiat Oncol Biol Phys, 2021, 109(5): 1483–1494. doi: 10.1016/j.ijrobp.2020.11.052
    [35]
    Lange-Consiglio A, Capra E, Herrera V, et al. Application of perinatal derivatives in ovarian diseases[J]. Front Bioeng Biotechnol, 2022, 10: 811875. doi: 10.3389/fbioe.2022.811875
    [36]
    Jing X, Xie M, Ding K, et al. Exosome-transmitted miR-769-5p confers cisplatin resistance and progression in gastric cancer by targeting CASP9 and promoting the ubiquitination degradation of p53[J]. Clin Transl Med, 2022, 12(5): e780. doi: 10.1002/ctm2.780
    [37]
    Galluzzi L, Senovilla L, Vitale I, et al. Molecular mechanisms of cisplatin resistance[J]. Oncogene, 2012, 31(15): 1869–1883. doi: 10.1038/onc.2011.384
    [38]
    Low WK, Kong SWW, Tan MGK. Ototoxicity from combined Cisplatin and radiation treatment: an in vitro study[J]. Int J Otolaryngol, 2010, 2010: 523976. doi: 10.1155/2010/523976
    [39]
    Zhou J, Yao Z, Zheng Z, et al. G-MDSCs-derived exosomal miRNA-143-3p promotes proliferation via targeting of ITM2B in lung cancer[J]. Onco Targets Ther, 2020, 13: 9701–9719. doi: 10.2147/OTT.S256378
    [40]
    Martins F, Santos I, da Cruz e silva OAB, et al. The role of the integral type II transmembrane protein BRI2 in health and disease[J]. Cell Mol Life Sci, 2021, 78(21-22): 6807–6822. doi: 10.1007/s00018-021-03932-5
  • Related Articles

    [1]Xu Han, Wen Li, Changying Chen, Jiahui Liu, Junxiang Sun, Feifan Wang, Chao Wang, Jialing Mu, Xincheng Gu, Fangyuan Liu, Hankun Xie, Song Yang, Chong Shen. Genetic variants and mRNA expression levels of KLF4 and KLF5 with hypertension: A combination of case-control study and cohort study[J]. The Journal of Biomedical Research, 2025, 39(1): 103-113. DOI: 10.7555/JBR.38.20240208
    [2]Miao Xu, Yan Gao, Wenjie Yin, Qinghuai Liu, Songtao Yuan. RNA-sequencing expression profile and functional analysis of retinal pigment epithelium in atrophic age-related macular degeneration[J]. The Journal of Biomedical Research, 2024, 38(5): 500-511. DOI: 10.7555/JBR.37.20230320
    [3]Yujuan Zhang, Kai Lu, Xu Wu, Hanting Liu, Junyi Xin, Xiaowei Wang, Weida Gong, Qinghong Zhao, Meilin Wang, Haiyan Chu, Mulong Du, Guoquan Tao, Zhengdong Zhang. Genetic variants in the Hedgehog signaling pathway genes are associated with gastric cancer risk in a Chinese Han population[J]. The Journal of Biomedical Research, 2022, 36(1): 22-31. DOI: 10.7555/JBR.35.20210091
    [4]Kai Wang, Zhongming Li, Wenjie Ma, Yan Sun, Xianling Liu, Lijun Qian, Jian Hong, Dasheng Lu, Jing Zhang, Di Xu. Construction of miRNA-mRNA network reveals crucial miRNAs and genes in acute myocardial infarction[J]. The Journal of Biomedical Research, 2021, 35(6): 425-435. DOI: 10.7555/JBR.35.20210088
    [5]Tiwari-Heckler Shilpa, Jiang Z. Gordon, Popov Yury, J. Mukamal Kenneth. Daily high-dose aspirin does not lower APRI in the Aspirin-Myocardial Infarction Study[J]. The Journal of Biomedical Research, 2020, 34(2): 139-142. DOI: 10.7555/JBR.33.20190041
    [6]Sun Meiqing, Ding Zhanlin, Wang Hong, Yu Guangping, Feng Zhe, Li Bingzhi, Li Penghui. Gelatin filter capture-based high-throughput sequencing analysis of microbial diversity in haze particulate matter[J]. The Journal of Biomedical Research, 2019, 33(6): 414-421. DOI: 10.7555/JBR.33.20180121
    [7]Minbo Zang, Qiao Zhou, Yunfei Zhu, Mingxi Liu, Zuomin Zhou. Effects of chemotherapeutic agent bendamustine for nonhodgkin lymphoma on spermatogenesis in mice[J]. The Journal of Biomedical Research, 2018, 32(6): 442-453. DOI: 10.7555/JBR.31.20170023
    [8]Kaibo Lin, Shikun Zhang, Jieli Chen, Ding Yang, Mengyi Zhu, Eugene Yujun Xu. Generation and functional characterization of a conditional Pumilio2 null allele[J]. The Journal of Biomedical Research, 2018, 32(6): 434-441. DOI: 10.7555/JBR.32.20170117
    [9]Huanqiang Wang, Congying Yang, Siyuan Wang, Tian Wang, Jingling Han, Kai Wei, Fucun Liu, Jida Xu, Xianzhen Peng, Jianming Wang. Cell-free plasma hypermethylated CASZ1, CDH13 and ING2 are promising biomarkers of esophageal cancer[J]. The Journal of Biomedical Research, 2018, 32(6): 424-433. DOI: 10.7555/JBR.32.20170065
    [10]Sundeep?S.?Tumber, Hong?Liu. Epidural abscess after multiple lumbar punctures for labour epidural catheter placement[J]. The Journal of Biomedical Research, 2010, 24(4): 332-335. DOI: 10.1016/S1674-8301(10)60046-2
  • Cited by

    Periodical cited type(11)

    1. Yu F, Zhao LX, Chu S. TCHH as a Novel Prognostic Biomarker for Patients with Gastric Cancer by Bioinformatics Analysis. Clin Exp Gastroenterol, 2024, 17: 61-74. DOI:10.2147/CEG.S451676
    2. Li K, Qiu Y, Liu X, et al. Biomimetic Nanosystems for the Synergistic Delivery of miR-144/451a for Oral Squamous Cell Carcinoma. Balkan Med J, 2022, 39(3): 178-186. DOI:10.4274/balkanmedj.galenos.2022.2021-11-1
    3. Yu CC, Chan MWY, Lin HY, et al. IRAK2, an IL1R/TLR Immune Mediator, Enhances Radiosensitivity via Modulating Caspase 8/3-Mediated Apoptosis in Oral Squamous Cell Carcinoma. Front Oncol, 2021, 11: 647175. DOI:10.3389/fonc.2021.647175
    4. Amiri-Dashatan N, Koushki M, Jalilian A, et al. Integrated Bioinformatics Analysis of mRNAs and miRNAs Identified Potential Biomarkers of Oral Squamous Cell Carcinoma. Asian Pac J Cancer Prev, 2020, 21(6): 1841-1848. DOI:10.31557/APJCP.2020.21.6.1841
    5. Xu GQ, Li LH, Wei JN, et al. Identification and profiling of microRNAs expressed in oral buccal mucosa squamous cell carcinoma of Chinese hamster. Sci Rep, 2019, 9(1): 15616. DOI:10.1038/s41598-019-52197-3
    6. Li CY, Zhang WW, Xiang JL, et al. Integrated analysis highlights multiple long non‑coding RNAs and their potential roles in the progression of human esophageal squamous cell carcinoma. Oncol Rep, 2019, 42(6): 2583-2599. DOI:10.3892/or.2019.7377
    7. Zhong L, Liu Y, Wang K, et al. Biomarkers: paving stones on the road towards the personalized precision medicine for oral squamous cell carcinoma. BMC Cancer, 2018, 18(1): 911. DOI:10.1186/s12885-018-4806-7
    8. Willett CS, Wilson EM. Evolution of Melanoma Antigen-A11 (MAGEA11) During Primate Phylogeny. J Mol Evol, 2018, 86(3-4): 240-253. DOI:10.1007/s00239-018-9838-8
    9. Li J, Zhou D, Qiu W, et al. Application of Weighted Gene Co-expression Network Analysis for Data from Paired Design. Sci Rep, 2018, 8(1): 622. DOI:10.1038/s41598-017-18705-z
    10. Mallik S, Zhao Z. ConGEMs: Condensed Gene Co-Expression Module Discovery Through Rule-Based Clustering and Its Application to Carcinogenesis. Genes (Basel), 2017, 9(1): 7. DOI:10.3390/genes9010007
    11. Irimie AI, Braicu C, Pileczki V, et al. Knocking down of p53 triggers apoptosis and autophagy, concomitantly with inhibition of migration on SSC-4 oral squamous carcinoma cells. Mol Cell Biochem, 2016, 419(1-2): 75-82. DOI:10.1007/s11010-016-2751-9

    Other cited types(0)

Catalog

    Figures(7)  /  Tables(1)

    Article Metrics

    Article views (296) PDF downloads (98) Cited by(11)
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return