Volume 44 Issue 3
May  2023
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Rui-Can Cao, Yue Lv, Gang Lu, Hong-Bin Liu, Wuming Wang, Chunlai Tan, Xian-Wei Su, Zhiqiang Xiong, Jin-Long Ma, Wai-Yee Chan. Extracellular vesicles from iPSC-MSCs alleviate chemotherapy-induced mouse ovarian damage via the ILK-PI3K/AKT pathway. Zoological Research, 2023, 44(3): 620-635. doi: 10.24272/j.issn.2095-8137.2022.340
Citation: Rui-Can Cao, Yue Lv, Gang Lu, Hong-Bin Liu, Wuming Wang, Chunlai Tan, Xian-Wei Su, Zhiqiang Xiong, Jin-Long Ma, Wai-Yee Chan. Extracellular vesicles from iPSC-MSCs alleviate chemotherapy-induced mouse ovarian damage via the ILK-PI3K/AKT pathway. Zoological Research, 2023, 44(3): 620-635. doi: 10.24272/j.issn.2095-8137.2022.340

Extracellular vesicles from iPSC-MSCs alleviate chemotherapy-induced mouse ovarian damage via the ILK-PI3K/AKT pathway

doi: 10.24272/j.issn.2095-8137.2022.340
The raw RNA-seq data were deposited in the NCBI Sequence Read Archive (SRA) (BioProjectID PRJNA916119), GSA Database (Accession No. CRA009327), and Science Data Bank (DOI:10.57760/sciencedb.j00139.00048). The raw miRNA-seq data were deposited in the NCBI SRA (BioProjectID PRJNA915756), GSA Database (Accession No. HRA003686), and Science Data Bank (DOI 10.57760/sciencedb.j00139.00047).
Supplementary data to this article can be found online.
The authors declare that they have no competing interests.
W.Y.C., J.L.M., G.L., and R.C.C. contributed to project conception. J.L.M., G.L., H.B.L., and W.Y.C. contributed to funding acquisition. R.-C.C. conducted experiments. Y.L., R.C.C, X.W.S., and Z.Q.X. analyzed data and prepared the figures and manuscript. W.M.W., C.L.T., and Y.L. provided technical support. All authors read and approved the final version of the manuscript.
Funds:  This work was supported by the CUHK VC Discretionary Fund provided to the Hong Kong Branch of Chinese Academy of Science Center for Excellence in Animal Evolution and Genetics (Acc 8601011), the National Key R&D Program (2021YFC2700500), A-Smart Group to Shandong University and SDIVF R&D Centre Hong Kong, and Research Grants Council General Research Fund (Hong Kong Special Administrative Region Government) (14103418)
More Information
  • Chemotherapy can significantly reduce follicle counts in ovarian tissues and damage ovarian stroma, causing endocrine disorder, reproductive dysfunction, and primary ovarian insufficiency (POI). Recent studies have suggested that extracellular vesicles (EVs) secreted from mesenchymal stem cells (MSCs) exert therapeutic effects in various degenerative diseases. In this study, transplantation of EVs from human induced pluripotent stem cell-derived MSCs (iPSC-MSC-EVs) resulted in significant restoration of ovarian follicle numbers, improved granulosa cell proliferation, and inhibition of apoptosis in chemotherapy-damaged granulosa cells, cultured ovaries, and in vivo ovaries in mice. Mechanistically, treatment with iPSC-MSC-EVs resulted in up-regulation of the integrin-linked kinase (ILK) -PI3K/AKT pathway, which is suppressed during chemotherapy, most likely through the transfer of regulatory microRNAs (miRNAs) targeting ILK pathway genes. This work provides a framework for the development of advanced therapeutics to ameliorate ovarian damage and POI in female chemotherapy patients.
  • The raw RNA-seq data were deposited in the NCBI Sequence Read Archive (SRA) (BioProjectID PRJNA916119), GSA Database (Accession No. CRA009327), and Science Data Bank (DOI:10.57760/sciencedb.j00139.00048). The raw miRNA-seq data were deposited in the NCBI SRA (BioProjectID PRJNA915756), GSA Database (Accession No. HRA003686), and Science Data Bank (DOI 10.57760/sciencedb.j00139.00047).
    Supplementary data to this article can be found online.
    The authors declare that they have no competing interests.
    W.Y.C., J.L.M., G.L., and R.C.C. contributed to project conception. J.L.M., G.L., H.B.L., and W.Y.C. contributed to funding acquisition. R.-C.C. conducted experiments. Y.L., R.C.C, X.W.S., and Z.Q.X. analyzed data and prepared the figures and manuscript. W.M.W., C.L.T., and Y.L. provided technical support. All authors read and approved the final version of the manuscript.
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  • [1]
    Acconcia F, Barnes CJ, Singh RR, et al. 2007. Phosphorylation-dependent regulation of nuclear localization and functions of integrin-linked kinase. Proceedings of the National Academy of Sciences of the United States of America, 104(16): 6782−6787. doi: 10.1073/pnas.0701999104
    [2]
    Attwell S, Mills J, Troussard A, et al. 2003. Integration of cell attachment, cytoskeletal localization, and signaling by integrin-linked kinase (ILK), CH-ILKBP, and the tumor suppressor PTEN. Molecular Biology of the Cell, 14(12): 4813−4825. doi: 10.1091/mbc.e03-05-0308
    [3]
    Basu J, Ludlow JW. 2016. Exosomes for repair, regeneration and rejuvenation. Expert Opinion on Biological Therapy, 16(4): 489−506. doi: 10.1517/14712598.2016.1131976
    [4]
    Broekmans FJ, Knauff EAH, Te Velde ER, et al. 2007. Female reproductive ageing: current knowledge and future trends. Trends in Endocrinology & Metabolism, 18(2): 58−65.
    [5]
    Coulam CB, Adamson SC, Annegers JF. 1986. Incidence of premature ovarian failure. Obstetrics and Gynecology, 67(4): 604−606.
    [6]
    Dann EJ, Epelbaum R, Avivi I, et al. 2005. Fertility and ovarian function are preserved in women treated with an intensified regimen of cyclophosphamide, adriamycin, vincristine and prednisone (Mega-CHOP) for non-Hodgkin lymphoma. Human Reproduction, 20(8): 2247−2249. doi: 10.1093/humrep/dei018
    [7]
    Desmeules P, Devine PJ. 2006. Characterizing the ovotoxicity of cyclophosphamide metabolites on cultured mouse ovaries. Toxicological Sciences, 90(2): 500−509. doi: 10.1093/toxsci/kfj086
    [8]
    Ding CY, Qian CF, Hou SY, et al. 2020a. Exosomal miRNA-320a is released from hAMSCs and regulates SIRT4 to prevent reactive oxygen species generation in POI. Molecular Therapy Nucleic Acids, 21: 37−50. doi: 10.1016/j.omtn.2020.05.013
    [9]
    Ding CY, Zhu LP, Shen H, et al. 2020b. Exosomal miRNA-17–5p derived from human umbilical cord mesenchymal stem cells improves ovarian function in premature ovarian insufficiency by regulating SIRT7. Stem Cells, 38(9): 1137−1148. doi: 10.1002/stem.3204
    [10]
    Dominici M, Le Blanc K, Mueller I, et al. 2006. Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy, 8(4): 315−317. doi: 10.1080/14653240600855905
    [11]
    Eke I, Leonhardt F, Storch K, et al. 2009. The small molecule inhibitor QLT0267 Radiosensitizes squamous cell carcinoma cells of the head and neck. PLoS One, 4(7): e6434. doi: 10.1371/journal.pone.0006434
    [12]
    Fang CC, Chou TH, Huang JW, et al. 2018. The small molecule inhibitor QLT-0267 decreases the production of fibrin-induced inflammatory cytokines and prevents post-surgical peritoneal adhesions. Scientific Reports, 8(1): 9481. doi: 10.1038/s41598-018-25994-5
    [13]
    Fu X, He Y, Xie C, et al. 2008. Bone marrow mesenchymal stem cell transplantation improves ovarian function and structure in rats with chemotherapy-induced ovarian damage. Cytotherapy, 10(4): 353−363. doi: 10.1080/14653240802035926
    [14]
    Górska A, Mazur AJ. 2022. Integrin-linked kinase (ILK): the known vs. the unknown and perspectives. Cellular and Molecular Life Sciences:CMLS, 79(2): 100. doi: 10.1007/s00018-021-04104-1
    [15]
    Guo J, Shi LY, Gong XH, et al. 2016. Oocyte-dependent activation of MTOR in cumulus cells controls the development and survival of cumulus-oocyte complexes. Journal of Cell Science, 129(16): 3091−3103.
    [16]
    Harrell CR, Jovicic N, Djonov V, et al. 2019. Mesenchymal stem cell-derived exosomes and other extracellular vesicles as new remedies in the therapy of inflammatory diseases. Cells, 8(12): 1605. doi: 10.3390/cells8121605
    [17]
    Hehlgans S, Eke I, Cordes N. 2007. An essential role of integrin-linked kinase in the cellular radiosensitivity of normal fibroblasts during the process of cell adhesion and spreading. International Journal of Radiation Biology, 83(11–12): 769–779.
    [18]
    Helleday T, Petermann E, Lundin C, et al. 2008. DNA repair pathways as targets for cancer therapy. Nature Reviews Cancer, 8(3): 193−204. doi: 10.1038/nrc2342
    [19]
    Hu GW, Li Q, Niu X, et al. 2015. Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells attenuate limb ischemia by promoting angiogenesis in mice. Stem Cell Research & Therapy, 6(1): 10.
    [20]
    Huang BX, Lu JF, Ding CY, et al. 2018. Exosomes derived from human adipose mesenchymal stem cells improve ovary function of premature ovarian insufficiency by targeting SMAD. Stem Cell Research & Therapy, 9(1): 216.
    [21]
    Im M, Dagnino L. 2018. Protective role of integrin-linked kinase against oxidative stress and in maintenance of genomic integrity. Oncotarget, 9(17): 13637−13651. doi: 10.18632/oncotarget.24444
    [22]
    Jankowska K. 2017. Premature ovarian failure. Menopause Review/Przegląd Menopauzalny, 16(2): 51−56.
    [23]
    Jiao X, Ke HN, Qin YY, et al. 2018. Molecular genetics of premature ovarian insufficiency. Trends in Endocrinology & Metabolism, 29(11): 795−807.
    [24]
    Jing H, He XM, Zheng JH. 2018. Exosomes and regenerative medicine: state of the art and perspectives. Translational Research, 196: 1−16. doi: 10.1016/j.trsl.2018.01.005
    [25]
    Kalich-Philosoph L, Roness H, Carmely A, et al. 2013. Cyclophosphamide triggers follicle activation and "burnout"; AS101 prevents follicle loss and preserves fertility. Science Translational Medicine, 5(185): 185ra62.
    [26]
    Kang L, Mokshagundam S, Reuter B, Lark DS, Sneddon CC, Hennayake C, et al. 2016. Integrin-linked kinase in muscle is necessary for the development of insulin resistance in diet-induced obese mice. Diabetes, 65(6): 1590−1600. doi: 10.2337/db15-1434
    [27]
    Krämer A, Green J, Pollard J Jr, et al. 2014. Causal analysis approaches in ingenuity pathway analysis. Bioinformatics, 30(4): 523−530. doi: 10.1093/bioinformatics/btt703
    [28]
    Liu XM, Zhang YL, Ji SY, et al. 2017. Mitochondrial function regulated by mitoguardin-1/2 is crucial for ovarian endocrine functions and ovulation. Endocrinology, 158(11): 3988−3999. doi: 10.1210/en.2017-00487
    [29]
    Livak KJ, Schmittgen TD. 2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT Method. Methods, 25(4): 402−408. doi: 10.1006/meth.2001.1262
    [30]
    Lobb RJ, Becker M, Wen SW, et al. 2015. Optimized exosome isolation protocol for cell culture supernatant and human plasma. Journal of Extracellular Vesicles, 4(1): 27031. doi: 10.3402/jev.v4.27031
    [31]
    Meirow D, Biederman H, Anderson RA, et al. 2010. Toxicity of chemotherapy and radiation on female reproduction. Clinical Obstetrics and Gynecology, 53(4): 727−739. doi: 10.1097/GRF.0b013e3181f96b54
    [32]
    Nagelkerke A, Ojansivu M, Van Der Koog L, et al. 2021. Extracellular vesicles for tissue repair and regeneration: evidence, challenges and opportunities. Advanced Drug Delivery Reviews, 175: 113775. doi: 10.1016/j.addr.2021.04.013
    [33]
    Okita K, Matsumura Y, Sato Y, et al. 2011. A more efficient method to generate integration-free human iPS cells. Nature Methods, 8(5): 409−412. doi: 10.1038/nmeth.1591
    [34]
    Okita K, Yamakawa T, Matsumura Y, et al. 2013. An efficient nonviral method to generate integration-free human-induced pluripotent stem cells from cord blood and peripheral blood cells. Stem Cells, 31(3): 458−466. doi: 10.1002/stem.1293
    [35]
    Pedersen T, Peters H. 1968. Proposal for a classification of oocytes and follicles in the mouse ovary. Reproduction, 17(3): 555−557. doi: 10.1530/jrf.0.0170555
    [36]
    Persad S, Attwell S, Gray V, et al. 2000. Inhibition of integrin-linked kinase (ILK) suppresses activation of protein kinase B/Akt and induces cell cycle arrest and apoptosis of PTEN-mutant prostate cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 97(7): 3207−3212. doi: 10.1073/pnas.97.7.3207
    [37]
    Piasecka-Srader J, Blanco FF, Delman DH, et al. 2015. Tamoxifen prevents apoptosis and follicle loss from cyclophosphamide in cultured rat ovaries. Biology of Reproduction, 92(5): 132.
    [38]
    Qi X, Zhang JY, Yuan H, et al. 2016. Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells repair critical-sized bone defects through enhanced angiogenesis and osteogenesis in osteoporotic rats. International Journal of Biological Sciences, 12(7): 836−849. doi: 10.7150/ijbs.14809
    [39]
    Qin YY, Jiao X, Simpson JL, et al. 2015. Genetics of primary ovarian insufficiency: new developments and opportunities. Human Reproduction Update, 21(6): 787−808. doi: 10.1093/humupd/dmv036
    [40]
    Radeva G, Petrocelli T, Behrend E, et al. 1997. Overexpression of the integrin-linked kinase promotes anchorage-independent cell cycle progression. Journal of Biological Chemistry, 272(21): 13937−13944. doi: 10.1074/jbc.272.21.13937
    [41]
    Ranghino A, Bruno S, Bussolati B, et al. 2017. The effects of glomerular and tubular renal progenitors and derived extracellular vesicles on recovery from acute kidney injury. Stem Cell Research & Therapy, 8(1): 24.
    [42]
    Remmele W, Stegner HE. 1987. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe, 8(3): 138–140. (in German)
    [43]
    Sonigo C, Beau I, Binart N, et al. 2019. The impact of chemotherapy on the ovaries: molecular aspects and the prevention of ovarian damage. International Journal of Molecular Sciences, 20(21): 5342. doi: 10.3390/ijms20215342
    [44]
    Sun B, Ma YJ, Wang F, et al. 2019. miR-644–5p carried by bone mesenchymal stem cell-derived exosomes targets regulation of p53 to inhibit ovarian granulosa cell apoptosis. Stem Cell Research & Therapy, 10(1): 360.
    [45]
    Sun LP, Li D, Song K, et al. 2017. Exosomes derived from human umbilical cord mesenchymal stem cells protect against cisplatin-induced ovarian granulosa cell stress and apoptosis in vitro. Scientific Reports, 7(1): 2552.
    [46]
    Takahashi A, Yousif A, Hong LD, et al. 2021. Premature ovarian insufficiency: pathogenesis and therapeutic potential of mesenchymal stem cell. Journal of Molecular Medicine, 99(5): 637−650. doi: 10.1007/s00109-021-02055-5
    [47]
    Tang QM, Lu B, He J, et al. 2022. Exosomes-loaded thermosensitive hydrogels for corneal epithelium and stroma regeneration. Biomaterials, 280: 121320. doi: 10.1016/j.biomaterials.2021.121320
    [48]
    Tang YY, Zhou Y, Li HJ. 2021. Advances in mesenchymal stem cell exosomes: a review. Stem Cell Research & Therapy, 12(1): 71.
    [49]
    Vlachos IS, Zagganas K, Paraskevopoulou MD, et al. 2015. DIANA-miRPath v3.0: deciphering microRNA function with experimental support. Nucleic Acids Research, 43(W1): W460−W466. doi: 10.1093/nar/gkv403
    [50]
    Wang W, Luo SM, Ma JY, et al. 2019. Cytotoxicity and DNA damage caused from diazinon exposure by inhibiting the PI3K-AKT pathway in porcine ovarian granulosa cells. Journal of Agricultural and Food Chemistry, 67(1): 19−31. doi: 10.1021/acs.jafc.8b05194
    [51]
    Wang XF, Zhang ZQ, Yao C. 2011. Targeting integrin-linked kinase increases apoptosis and decreases invasion of myeloma cell lines and inhibits IL-6 and VEGF secretion from BMSCs. Medical Oncology, 28(4): 1596−1600. doi: 10.1007/s12032-010-9616-y
    [52]
    Wu CY, Dedhar S. 2001. Integrin-linked kinase (ILK) and its interactors: a new paradigm for the coupling of extracellular matrix to actin cytoskeleton and signaling complexes. The Journal of Cell Biology, 155(4): 505−510. doi: 10.1083/jcb.200108077
    [53]
    Xia YG, Ling XZ, Hu GW, et al. 2020. Small extracellular vesicles secreted by human iPSC-derived MSC enhance angiogenesis through inhibiting STAT3-dependent autophagy in ischemic stroke. Stem Cell Research & Therapy, 11(1): 313.
    [54]
    Yang ML, Lin L, Sha CL, et al. 2020. Bone marrow mesenchymal stem cell-derived exosomal miR-144–5p improves rat ovarian function after chemotherapy-induced ovarian failure by targeting PTEN. Laboratory Investigation, 100(3): 342−352. doi: 10.1038/s41374-019-0321-y
    [55]
    Yang ZL, Du X, Wang CL, et al. 2019. Therapeutic effects of human umbilical cord mesenchymal stem cell-derived microvesicles on premature ovarian insufficiency in mice. Stem Cell Research & Therapy, 10(1): 250.
    [56]
    Younes MN, Yigitbasi OG, Yazici YD, et al. 2007. Effects of the integrin-linked kinase inhibitor QLT0267 on squamous cell carcinoma of the head and neck. Archives of Otolaryngology-Head & Neck Surgery, 133(1): 15−23.
    [57]
    Zhang JY, Guan JJ, Niu X, et al. 2015. Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. Journal of Translational Medicine, 13: 49. doi: 10.1186/s12967-015-0417-0
    [58]
    Zhang QW, Bu SX, Sun JY, et al. 2017. Paracrine effects of human amniotic epithelial cells protect against chemotherapy-induced ovarian damage. Stem Cell Research & Therapy, 8(1): 270.
    [59]
    Zhang QW, Sun JY, Huang YT, et al. 2019. Human amniotic epithelial cell-derived exosomes restore ovarian function by transferring MicroRNAs against apoptosis. Molecular Therapy Nucleic Acids, 16: 407−418. doi: 10.1016/j.omtn.2019.03.008
    [60]
    Zhang WH, Ji H, Wang JL, et al. 2014. Garnulosa cells model tansfected by ENO1 overexpression adenovirus vector and the effect of ENO1 overexpression on progesterone secretion. Chinese Journal of Applied Physiology, 30(1): 85−88. (in Chinese)
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