Human amnion-derived mesenchymal stem cell (hAD-MSC) transplantation improves ovarian function in rats with premature ovarian insufficiency (POI) at least partly through a paracrine mechanism

Li Ling, Xiushan Feng, Tianqin Wei, Yan Wang, Yaping Wang, Ziling Wang, Dongyuan Tang, Yanjing Luo, Zhengai Xiong, Li Ling, Xiushan Feng, Tianqin Wei, Yan Wang, Yaping Wang, Ziling Wang, Dongyuan Tang, Yanjing Luo, Zhengai Xiong

Abstract

Background: Chemotherapy can induce premature ovarian insufficiency (POI) and reduce fertility in young female patients. Currently, there is no effective therapy for POI. Human amnion-derived mesenchymal stem cells (hAD-MSCs) may be a promising seed cell for regenerative medicine. This study investigated the effects and mechanisms of hAD-MSC transplantation on chemotherapy-induced POI in rats.

Methods: Chemotherapy-induced POI rat models were established by intraperitoneal injection of cyclophosphamide. Seventy-two female SD rats were randomly divided into control, POI, and hAD-MSC-treated groups. hAD-MSCs were labeled with PKH26 and injected into the tail veins of POI rats. To examine the underlying mechanisms, the differentiation of transplanted hAD-MSCs in the POI ovaries was analyzed by immunofluorescent staining. The in vitro expression of growth factors secreted by hAD-MSCs in hAD-MSC-conditioned media (hAD-MSC-CM) was analyzed by ELISA. Sixty female SD rats were divided into control, POI, and hAD-MSC-CM-treated groups, and hAD-MSC-CM was injected into the bilateral ovaries of POI rats. After hAD-MSC transplantation or hAD-MSC-CM injection, serum sex hormone levels, estrous cycles, ovarian pathological changes, follicle counts, granulosa cell (GC) apoptosis, and Bcl-2, Bax, and VEGF expression in ovaries were examined.

Results: PKH26-labeled hAD-MSCs mainly homed to ovaries after transplantation. hAD-MSC transplantation reduced ovarian injury and improved ovarian function in rats with POI. Transplanted hAD-MSCs were only located in the interstitium of ovaries, rather than in follicles, and did not express the typical markers of oocytes and GCs, which are ZP3 and FSHR, respectively. hAD-MSCs secreted FGF2, IGF-1, HGF, and VEGF, and those growth factors were detected in the hAD-MSC-CM. hAD-MSC-CM injection improved the local microenvironment of POI ovaries, leading to a decrease in Bax expression and an increase in Bcl-2 and endogenous VEGF expression in ovarian cells, which inhibited chemotherapy-induced GC apoptosis, promoted angiogenesis and regulated follicular development, thus partly reducing ovarian injury and improving ovarian function in rats with POI.

Conclusions: hAD-MSC transplantation can improve ovarian function in rats with chemotherapy-induced POI at least partly through a paracrine mechanism. The presence of a paracrine mechanism accounting for hAD-MSC-mediated recovery of ovarian function might be attributed to the growth factors secreted by hAD-MSCs.

Keywords: Conditioned media (CM); Growth factors; Human amnion-derived mesenchymal stem cells (hAD-MSCs); Paracrine; Premature ovarian insufficiency (POI).

Conflict of interest statement

Authors’ information

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Ethics approval and consent to participate

The research was in compliance with the Helsinki Declaration and approved by the Ethics Committee of the Second Affiliated Hospital of Chongqing Medical University. Written informed consent was obtained from all donors before collecting amnion. Animal experimental protocols were approved by the Ethics Committee of the Second Affiliated Hospital of Chongqing Medical University (permit number 2016-044).

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Not applicable

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1
Fig. 1
Experimental protocols and schematic. a A schematic of the experimental procedure used to explore the effects and mechanisms of hAD-MSC transplantation on chemotherapy-induced POI in rats. b Injection of CM into ovaries of SD rats. c The estrous cycle of SD rats (× 100). The yellow arrows indicate nucleated epithelial cells, the red arrows indicate cornified epithelium and the blue arrows indicate leukocytes. Scale bars, 100 μm
Fig. 2
Fig. 2
Morphology of hAD-MSCs (a × 40, b × 100, c × 200)
Fig. 3
Fig. 3
Tracking of hAD-MSCs in vivo. a, b PKH26-labeled hAD-MSCs showed red fluorescence in vitro (a × 100) and in vivo (b × 800). c The labeling rate of PKH26-labeled hAD-MSCs was analyzed using flow cytometry. d The growth curves of PKH26-labeled and unlabeled hAD-MSCs were analyzed using a CCK-8 assay (n = 6). e, f Transplanted PKH26-labeled hAD-MSCs were observed at 24 h after cell transplantation in ovaries (e × 100) and other organs (f × 100) of SD rats in the hAD-MSC-treated group. *P < 0.05 and **P < 0.01. Scale bars, 100 μm
Fig. 4
Fig. 4
Changes in ovarian function and histology after hAD-MSC transplantation. a The percentage of rats with abnormal estrous cycles was observed at 1, 4, and 8 weeks after hAD-MSC transplantation. b–d Serum levels of AMH (b), FSH (c), and E2 (d) were evaluated at 0, 2, 4, and 8 weeks after hAD-MSC transplantation. e, f Changes in the histology of ovaries were analyzed using HE staining (e × 40), and the number of follicles at different stages was counted and compared (f) in the three groups at 4 weeks after hAD-MSC transplantation. *P < 0.05 and **P < 0.01. Scale bars, 100 μm
Fig. 5
Fig. 5
Tracking the differentiation of hAD-MSCs in ovaries. The expression of ZP3 (a × 100 and × 800) and FSHR (b × 100 and × 800) in hAD-MSCs was observed at 8 weeks after hAD-MSC transplantation in ovaries. The yellow arrows indicate transplanted hAD-MSCs. Scale bars, 100 μm; Scale bars, 20 μm
Fig. 6
Fig. 6
Analysis of CM derived from hAD-MSCs. The protein concentration (a) and molecular weight distribution of proteins (b) and cytokines secreted by hAD-MSCs (c) in CM were analyzed. *P < 0.05 and **P < 0.01
Fig. 7
Fig. 7
Changes in ovarian function and histology after hAD-MSC-CM injection. a The percentage of rats with abnormal estrous cycles was observed at 2, 4, and 8 weeks after CM injection. b–d Serum levels of AMH (b), FSH (c), and E2 (d) were evaluated at 0, 2, 4, and 8 weeks after CM injection. e, f Changes in the histology of ovaries were analyzed using HE staining (e × 40), and the number of follicles at different stages was counted and compared (f) in the three groups at 4 weeks after CM injection. *P < 0.05 and **P < 0.01. Scale bars, 100 μm
Fig. 8
Fig. 8
The effects of hAD-MSC-CM on chemotherapy-induced ovarian GC apoptosis in POI rats. Representative images of the TUNEL apoptosis assay for ovaries from the three groups are shown (× 40 and × 400). Dark brown cells representing ovarian apoptotic GCs are indicated by black arrows. Scale bars, 100 μm; Scale bars, 20 μm
Fig. 9
Fig. 9
The effects of hAD-MSC-CM on the expression of Bcl-2, Bax, and VEGF in the ovaries of POI rats. Representative immunohistochemistry images (a × 40 and × 400) and semiquantitative analysis of Bax, Bcl-2, and VEGF expression (b–d) of ovaries from the three groups are shown (n = 10). Immunostained cells (brown cells) are indicated by black arrows. Each dot in graphs b, c, and d represents the value across ten HPFs randomly chosen from five sections in each group. The bars and error bars indicate the medians and ranges, respectively. *P < 0.05 and **P < 0.01. Scale bars, 100 μm; Scale bars, 20 μm

References

    1. European Society for Human R, Embryology 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(5):926–937.
    1. Sullivan SD, Sarrel PM, Nelson LM. Hormone replacement therapy in young women with primary ovarian insufficiency and early menopause. Fertil Steril. 2016;106(7):1588–1599.
    1. Cho SH, Ahn EH, An HJ, Kim JH, Ko JJ, Kim YR, et al. Association of miR-938G>A Polymorphisms with Primary Ovarian Insufficiency (POI)-Related Gene Expression. Int J Mol Sci. 2017;18(6):1-9.
    1. Lai D, Wang F, Chen Y, Wang L, Wang Y, Cheng W. Human amniotic fluid stem cells have a potential to recover ovarian function in mice with chemotherapy-induced sterility. BMC Dev Biol. 2013;13:34.
    1. Barr RD. Adolescents, young adults, and cancer--the international challenge. Cancer. 2011;117(10 Suppl):2245–2249.
    1. Gorman JR, Bailey S, Pierce JP, Su HI. How do you feel about fertility and parenthood? The voices of young female cancer survivors. J Cancer Surviv. 2012;6(2):200–209.
    1. Robinson RD, Knudtson JF. Fertility preservation in patients receiving chemotherapy or radiotherapy. Mo Med. 2014;111(5):434–438.
    1. Meirow D, Nugent D. The effects of radiotherapy and chemotherapy on female reproduction. Hum Reprod Update. 2001;7(6):535–543.
    1. Wang Z, Wang Y, Yang T, Li J, Yang X. Study of the reparative effects of menstrual-derived stem cells on premature ovarian failure in mice. Stem Cell Res Ther. 2017;8(1):11.
    1. Liu J, Zhang H, Zhang Y, Li N, Wen Y, Cao F, et al. Homing and restorative effects of bone marrow-derived mesenchymal stem cells on cisplatin injured ovaries in rats. Mol Cells. 2014;37(12):865–872.
    1. Wang S, Yu L, Sun M, Mu S, Wang C, Wang D, et al. The therapeutic potential of umbilical cord mesenchymal stem cells in mice premature ovarian failure. Biomed Res Int. 2013;2013:690491.
    1. Gerson SL. Mesenchymal stem cells: no longer second class marrow citizens. Nat Med. 1999;5(3):262–264.
    1. Samiec M, Opiela J, Lipinski D, Romanek J. Trichostatin A-mediated epigenetic transformation of adult bone marrow-derived mesenchymal stem cells biases the in vitro developmental capability, quality, and pluripotency extent of porcine cloned embryos. Biomed Res Int. 2015;2015:814686.
    1. Kisiel AH, McDuffee LA, Masaoud E, Bailey TR, Esparza Gonzalez BP, Nino-Fong R. Isolation, characterization, and in vitro proliferation of canine mesenchymal stem cells derived from bone marrow, adipose tissue, muscle, and periosteum. Am J Vet Res. 2012;73(8):1305–1317.
    1. Ling L, Wei T, He L, Wang Y, Wang Y, Feng X, et al. Low-intensity pulsed ultrasound activates ERK1/2 and PI3K-Akt signalling pathways and promotes the proliferation of human amnion-derived mesenchymal stem cells. Cell Prolif. 2017;50(6):1-12.
    1. Diaz-Prado S, Muinos-Lopez E, Hermida-Gomez T, Rendal-Vazquez ME, Fuentes-Boquete I, de Toro FJ, et al. Multilineage differentiation potential of cells isolated from the human amniotic membrane. J Cell Biochem. 2010;111(4):846–857.
    1. Diaz-Prado S, Muinos-Lopez E, Hermida-Gomez T, Rendal-Vazquez ME, Fuentes-Boquete I, de Toro FJ, et al. Isolation and characterization of mesenchymal stem cells from human amniotic membrane. Tissue engineering part C. Methods. 2011;17(1):49–59.
    1. Soncini M, Vertua E, Gibelli L, Zorzi F, Denegri M, Albertini A, et al. Isolation and characterization of mesenchymal cells from human fetal membranes. J Tissue Eng Regen Med. 2007;1(4):296–305.
    1. Parolini O, Alviano F, Bagnara GP, Bilic G, Buhring HJ, Evangelista M, et al. Concise review: isolation and characterization of cells from human term placenta: outcome of the first international Workshop on Placenta Derived Stem Cells. Stem Cells. 2008;26(2):300–311.
    1. Fu X, He Y, Wang X, Peng D, Chen X, Li X, et al. Overexpression of miR-21 in stem cells improves ovarian structure and function in rats with chemotherapy-induced ovarian damage by targeting PDCD4 and PTEN to inhibit granulosa cell apoptosis. Stem Cell Res Ther. 2017;8(1):187.
    1. Byers SL, Wiles MV, Dunn SL, Taft RA. Mouse estrous cycle identification tool and images. PLoS One. 2012;7(4):e35538.
    1. Myers M, Britt KL, Wreford NG, Ebling FJ, Kerr JB. Methods for quantifying follicular numbers within the mouse ovary. Reproduction. 2004;127(5):569–580.
    1. Song D, Zhong Y, Qian C, Zou Q, Ou J, Shi Y, et al. Human umbilical cord mesenchymal stem cells therapy in cyclophosphamide-induced premature ovarian failure rat model. Biomed Res Int. 2016;2016:2517514.
    1. Ma Y, Ma L, Guo Q, Zhang S. Expression of bone morphogenetic protein-2 and its receptors in epithelial ovarian cancer and their influence on the prognosis of ovarian cancer patients. J Exp Clin Cancer Res. 2010;29:85.
    1. Xu X, Tan Y, Jiang G, Chen X, Lai R, Zhang L, et al. Effects of Bushen Tianjing Recipe in a rat model of tripterygium glycoside-induced premature ovarian failure. Chin Med. 2017;12:10.
    1. Bedoschi G, Navarro PA, Oktay K. Chemotherapy-induced damage to ovary: mechanisms and clinical impact. Future Oncol. 2016;12(20):2333–2344.
    1. Ezoe K, Murata N, Yabuuchi A, Okuno T, Kobayashi T, Kato O, et al. Long-term adverse effects of cyclophosphamide on follicular growth and angiogenesis in mouse ovaries. Reprod Biol. 2014;14(3):238–242.
    1. Yao X, Guo Y, Wang Q, Xu M, Zhang Q, Li T, et al. The paracrine effect of transplanted human amniotic epithelial cells on ovarian function improvement in a mouse model of chemotherapy-induced primary ovarian insufficiency. Stem Cells Int. 2016;2016:4148923.
    1. Takehara Y, Yabuuchi A, Ezoe K, Kuroda T, Yamadera R, Sano C, et al. The restorative effects of adipose-derived mesenchymal stem cells on damaged ovarian function. Lab Investig. 2013;93(2):181–193.
    1. Zhang Q, Bu S, Sun J, Xu M, Yao X, He K, et al. Paracrine effects of human amniotic epithelial cells protect against chemotherapy-induced ovarian damage. Stem Cell Res Ther. 2017;8(1):270.
    1. Ranganath SH, Levy O, Inamdar MS, Karp JM. Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell. 2012;10(3):244–258.
    1. Ferrara N. Vascular endothelial growth factor. Arterioscler Thromb Vasc Biol. 2009;29(6):789–791.
    1. Li Q, Szatmary P, Liu Y, Ding Z, Zhou J, Sun Y, et al. Orthotopic transplantation of cryopreserved mouse ovaries and gonadotrophin releasing hormone analogues in the restoration of function following chemotherapy-induced ovarian damage. PLoS One. 2015;10(3):e0120736.
    1. Simao VA, Berloffa Belardin L, Araujo Leite GA, de Almeida Chuffa LG, Camargo IC. Effects of different doses of nandrolone decanoate on estrous cycle and ovarian tissue of rats after treatment and recovery periods. Int J Exp Pathol. 2015;96(5):338–349.
    1. Ling L, Feng X, Wei T, Wang Y, Wang Y, Zhang W, et al. Effects of low-intensity pulsed ultrasound (LIPUS)-pretreated human amnion-derived mesenchymal stem cell (hAD-MSC) transplantation on primary ovarian insufficiency in rats. Stem Cell Res Ther. 2017;8(1):283.
    1. Wang Z, Wang Y, Yang T, Li J, Yang X. Erratum to: Study of the reparative effects of menstrual-derived stem cells on premature ovarian failure in mice. Stem Cell Res Ther. 2017;8(1):49.
    1. Lazaros LA, Hatzi EG, Pamporaki CE, Sakaloglou PI, Xita NV, Markoula SI, et al. The ovarian response to standard gonadotrophin stimulation depends on FSHR, SHBG and CYP19 gene synergism. J Assist Reprod Genet. 2012;29(11):1185–1191.
    1. Durlinger AL, Visser JA, Themmen AP. Regulation of ovarian function: the role of anti-Mullerian hormone. Reproduction. 2002;124(5):601–609.
    1. Meirow D, Dor J, Kaufman B, Shrim A, Rabinovici J, Schiff E, et al. Cortical fibrosis and blood-vessels damage in human ovaries exposed to chemotherapy. Potential mechanisms of ovarian injury. Hum Reprod. 2007;22(6):1626–1633.
    1. Kuchroo P, Dave V, Vijayan A, Viswanathan C, Ghosh D. Paracrine factors secreted by umbilical cord-derived mesenchymal stem cells induce angiogenesis in vitro by a VEGF-independent pathway. Stem Cells Dev. 2015;24(4):437–450.
    1. Kelkar AA, Butler J, Schelbert EB, Greene SJ, Quyyumi AA, Bonow RO, et al. Mechanisms contributing to the progression of ischemic and nonischemic dilated cardiomyopathy: possible modulating effects of paracrine activities of stem cells. J Am Coll Cardiol. 2015;66(18):2038–2047.
    1. Crisostomo PR, Markel TA, Wang Y, Meldrum DR. Surgically relevant aspects of stem cell paracrine effects. Surgery. 2008;143(5):577–581.
    1. Kotomin I, Valtink M, Hofmann K, Frenzel A, Morawietz H, Werner C, et al. Sutureless fixation of amniotic membrane for therapy of ocular surface disorders. PLoS One. 2015;10(5):e0125035.
    1. Koizumi NJ, Inatomi TJ, Sotozono CJ, Fullwood NJ, Quantock AJ, Kinoshita S. Growth factor mRNA and protein in preserved human amniotic membrane. Curr Eye Res. 2000;20(3):173–177.
    1. Chowdhury I, Branch A, Mehrabi S, Ford BD, Thompson WE. Gonadotropin-dependent neuregulin-1 signaling regulates female rat ovarian granulosa cell survival. Endocrinology. 2017;158(10):3647–3660.
    1. Richards JS, Pangas SA. The ovary: basic biology and clinical implications. J Clin Invest. 2010;120(4):963–972.
    1. Babitha V, Yadav VP, Chouhan VS, Hyder I, Dangi SS, Gupta M, et al. Luteinizing hormone, insulin like growth factor-1, and epidermal growth factor stimulate vascular endothelial growth factor production in cultured bubaline granulosa cells. Gen Comp Endocrinol. 2014;198:1–12.
    1. Zachow R, Uzumcu M. The hepatocyte growth factor system as a regulator of female and male gonadal function. J Endocrinol. 2007;195(3):359–371.
    1. Hunter MG, Robinson RS, Mann GE, Webb R. Endocrine and paracrine control of follicular development and ovulation rate in farm species. Anim Reprod Sci. 2004;82-83:461–477.
    1. Shimizu T, Jiang JY, Sasada H, Sato E. Changes of messenger RNA expression of angiogenic factors and related receptors during follicular development in gilts. Biol Reprod. 2002;67(6):1846–1852.
    1. Tremblay PG, Sirard MA. Transcriptomic analysis of gene cascades involved in protein kinase A and C signaling in the KGN line of human ovarian granulosa tumor cells. Biol Reprod. 2017;96(4):855–865.
    1. Mao J, Smith MF, Rucker EB, Wu GM, McCauley TC, Cantley TC, et al. Effect of epidermal growth factor and insulin-like growth factor I on porcine preantral follicular growth, antrum formation, and stimulation of granulosal cell proliferation and suppression of apoptosis in vitro. J Anim Sci. 2004;82(7):1967–1975.
    1. Kamat BR, Brown LF, Manseau EJ, Senger DR, Dvorak HF. Expression of vascular permeability factor/vascular endothelial growth factor by human granulosa and theca lutein cells. Role in corpus luteum development. Am J Pathol. 1995;146(1):157–165.
    1. Berisha B, Schams D, Kosmann M, Amselgruber W, Einspanier R. Expression and localisation of vascular endothelial growth factor and basic fibroblast growth factor during the final growth of bovine ovarian follicles. J Endocrinol. 2000;167(3):371–382.
    1. Karsan A, Yee E, Poirier GG, Zhou P, Craig R, Harlan JM. Fibroblast growth factor-2 inhibits endothelial cell apoptosis by Bcl-2-dependent and independent mechanisms. Am J Pathol. 1997;151(6):1775–1784.
    1. Kosaka N, Sudo N, Miyamoto A, Shimizu T. Vascular endothelial growth factor (VEGF) suppresses ovarian granulosa cell apoptosis in vitro. Biochem Biophys Res Commun. 2007;363(3):733–737.
    1. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298–307.
    1. Seghezzi G, Patel S, Ren CJ, Gualandris A, Pintucci G, Robbins ES, et al. Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: an autocrine mechanism contributing to angiogenesis. J Cell Biol. 1998;141(7):1659–1673.
    1. Mishra SR, Thakur N, Somal A, Parmar MS, Reshma R, Rajesh G, et al. Expression and localization of fibroblast growth factor (FGF) family in buffalo ovarian follicle during different stages of development and modulatory role of FGF2 on steroidogenesis and survival of cultured buffalo granulosa cells. Res Vet Sci. 2016;108:98–111.
    1. Martinez-Chequer JC, Stouffer RL, Hazzard TM, Patton PE, Molskness TA. Insulin-like growth factors-1 and -2, but not hypoxia, synergize with gonadotropin hormone to promote vascular endothelial growth factor-A secretion by monkey granulosa cells from preovulatory follicles. Biol Reprod. 2003;68(4):1112–1118.
    1. Nakamura T, Mizuno S. The discovery of hepatocyte growth factor (HGF) and its significance for cell biology, life sciences and clinical medicine. Proceedings of the Japan Academy Series B, Physical and Biol Sci. 2010;86(6):588–610.
    1. Zachow RJ, Woolery JK. Effects of hepatocyte growth factor on cyclic nucleotide-dependent signaling and steroidogenesis in rat ovarian granulosa cells in vitro. Biol Reprod. 2002;67(2):454–459.
    1. Zachow RJ, Weitsman SR, Magoffin DA. Hepatocyte growth factor regulates ovarian theca-interstitial cell differentiation and androgen production. Endocrinology. 1997;138(2):691–697.
    1. Uzumcu M, Pan Z, Chu Y, Kuhn PE, Zachow R. Immunolocalization of the hepatocyte growth factor (HGF) system in the rat ovary and the anti-apoptotic effect of HGF in rat ovarian granulosa cells in vitro. Reproduction. 2006;132(2):291–299.
    1. Guglielmo MC, Ricci G, Catizone A, Barberi M, Galdieri M, Stefanini M, et al. The effect of hepatocyte growth factor on the initial stages of mouse follicle development. J Cell Physiol. 2011;226(2):520–529.
    1. Reed JC. Bcl-2 and the regulation of programmed cell death. J Cell Biol. 1994;124(1–2):1–6.
    1. Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 1988;335(6189):440–442.
    1. Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993;74(4):609–619.
    1. Sai T, Goto Y, Yoshioka R, Maeda A, Matsuda F, Sugimoto M, et al. Bid and Bax are involved in granulosa cell apoptosis during follicular atresia in porcine ovaries. J Reprod Dev. 2011;57(3):421–427.
    1. Babitha V, Panda RP, Yadav VP, Chouhan VS, Dangi SS, Khan FA, et al. Amount of mRNA and localization of vascular endothelial growth factor and its receptors in the ovarian follicle during estrous cycle of water buffalo (Bubalus bubalis) Anim Reprod Sci. 2013;137(3–4):163–176.
    1. Mishra SR, Bharati J, Rajesh G, Chauhan VS, Taru Sharma G, Bag S, et al. Fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor A (VEGFA) synergistically promote steroidogenesis and survival of cultured buffalo granulosa cells. Anim Reprod Sci. 2017;179:88–97.
    1. Abramovich D, Parborell F, Tesone M. Effect of a vascular endothelial growth factor (VEGF) inhibitory treatment on the folliculogenesis and ovarian apoptosis in gonadotropin-treated prepubertal rats. Biol Reprod. 2006;75(3):434–441.
    1. Fu X, He Y, Xie C, Liu W. Bone marrow mesenchymal stem cell transplantation improves ovarian function and structure in rats with chemotherapy-induced ovarian damage. Cytotherapy. 2008;10(4):353–363.
    1. Ellison GM, Torella D, Dellegrottaglie S, Perez-Martinez C, Perez de Prado A, Vicinanza C, et al. Endogenous cardiac stem cell activation by insulin-like growth factor-1/hepatocyte growth factor intracoronary injection fosters survival and regeneration of the infarcted pig heart. J Am Coll Cardiol. 2011;58(9):977–986.
    1. Tang Y, Li Q, Meng F, Huang X, Li C, Zhou X, et al. Therapeutic potential of HGF-expressing human umbilical cord mesenchymal stem cells in mice with acute liver failure. Int J Hepatol. 2016;2016:5452487.
    1. Liu J, Wu P, Wang Y, Du Y, A N, Liu S, et al. Ad-HGF improves the cardiac remodeling of rat following myocardial infarction by upregulating autophagy and necroptosis and inhibiting apoptosis. Am J Transl Res. 2016;8(11):4605–4627.
    1. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246(4935):1306–1309.
    1. Irusta G, Abramovich D, Parborell F, Tesone M. Direct survival role of vascular endothelial growth factor (VEGF) on rat ovarian follicular cells. Mol Cell Endocrinol. 2010;325(1–2):93–100.
    1. Danforth DR, Arbogast LK, Ghosh S, Dickerman A, Rofagha R, Friedman CI. Vascular endothelial growth factor stimulates preantral follicle growth in the rat ovary. Biol Reprod. 2003;68(5):1736–1741.

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