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ISSN (Print): 1566-5232
ISSN (Online): 1875-5631

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Mini-Review Article

The Functions and Application Prospects of Hepatocyte Growth Factor in Reproduction

Author(s): Xin Mi, Caiyi Chen, Chen Feng, Yingying Qin, Zi-Jiang Chen, Yajuan Yang* and Shidou Zhao*

Volume 24, Issue 5, 2024

Published on: 23 February, 2024

Page: [347 - 355] Pages: 9

DOI: 10.2174/0115665232291010240221104445

Price: $65

Abstract

Hepatocyte growth factor (HGF) is expressed in multiple systems and mediates a variety of biological activities, such as mitosis, motility, and morphogenesis. A growing number of studies have revealed the expression patterns and functions of HGF in ovarian and testicular physiology from the prenatal to the adult stage. HGF regulates folliculogenesis and steroidogenesis by modulating the functions of theca cells and granulosa cells in the ovary. It also mediates somatic cell proliferation and steroidogenesis, thereby affecting spermatogenesis in males. In addition to its physiological effects on the reproductive system, HGF has shown advantages in preclinical studies over recent years for the treatment of male and female infertility, particularly in women with premature ovarian insufficiency. This review aims to summarize the pleiotropic functions of HGF in the reproductive system and to provide prospects for its clinical application.

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Graphical Abstract

[1]
Nakamura T, Sakai K, Nakamura T, Matsumoto K. Hepatocyte growth factor twenty years on: Much more than a growth factor. J Gastroenterol Hepatol 2011; 26(1): 188-202.
[http://dx.doi.org/10.1111/j.1440-1746.2010.06549.x] [PMID: 21199531]
[2]
Seid T, Hagiya M, Shimonishi M, Nakamura T, Shimizu S. Organization of the human hepatocyte growth factor-encoding gene. Gene 1991; 102(2): 213-9.
[http://dx.doi.org/10.1016/0378-1119(91)90080-U] [PMID: 1831432]
[3]
Nakamura T, Mizuno S. The discovery of hepatocyte growth factor (HGF) and its significance for cell biology, life sciences and clinical medicine. Proc Jpn Acad, Ser B, Phys Biol Sci 2010; 86(6): 588-610.
[http://dx.doi.org/10.2183/pjab.86.588] [PMID: 20551596]
[4]
Uchikawa E, Chen Z, Xiao GY, Zhang X, Bai X. Structural basis of the activation of c-MET receptor. Nat Commun 2021; 12(1): 4074.
[http://dx.doi.org/10.1038/s41467-021-24367-3] [PMID: 34210960]
[5]
Linossi EM, Estevam GO, Oshima M, Fraser JS, Collisson EA, Jura N. State of the structure address on MET receptor activation by HGF. Biochem Soc Trans 2021; 49(2): 645-61.
[http://dx.doi.org/10.1042/BST20200394] [PMID: 33860789]
[6]
Stewart F. Roles of mesenchymal-epithelial interactions and hepatocyte growth factor-scatter factor (HGF-SF) in placental development. Rev Reprod 1996; 1(3): 144-8.
[http://dx.doi.org/10.1530/ror.0.0010144] [PMID: 9414451]
[7]
Zhao Y, Ye W, Wang YD, Chen WD. HGF/c-Met: A key promoter in liver regeneration. Front Pharmacol 2022; 13: 808855.
[http://dx.doi.org/10.3389/fphar.2022.808855] [PMID: 35370682]
[8]
Gallo S, Sala V, Gatti S, Crepaldi T. Cellular and molecular mechanisms of HGF/Met in the cardiovascular system. Clin Sci 2015; 129(12): 1173-93.
[http://dx.doi.org/10.1042/CS20150502] [PMID: 26561593]
[9]
Matsumoto K, Funakoshi H, Takahashi H, Sakai K. HGF–Met pathway in regeneration and drug discovery. Biomedicines 2014; 2(4): 275-300.
[http://dx.doi.org/10.3390/biomedicines2040275] [PMID: 28548072]
[10]
Desole C, Gallo S, Vitacolonna A, et al. HGF and MET: From brain development to neurological disorders. Front Cell Dev Biol 2021; 9: 683609.
[http://dx.doi.org/10.3389/fcell.2021.683609] [PMID: 34179015]
[11]
Zachow R, Uzumcu M. The hepatocyte growth factor system as a regulator of female and male gonadal function. J Endocrinol 2007; 195(3): 359-71.
[http://dx.doi.org/10.1677/JOE-07-0466] [PMID: 18000299]
[12]
Ito M, Harada T, Tanikawa M, Fujii A, Shiota G, Terakawa N. Hepatocyte growth factor and stem cell factor involvement in paracrine interplays of theca and granulosa cells in the human ovary. Fertil Steril 2001; 75(5): 973-9.
[http://dx.doi.org/10.1016/S0015-0282(01)01747-2] [PMID: 11334911]
[13]
Parrott JA, Vigne JL, Chu BZ, Skinner MK. Mesenchymal-epithelial interactions in the ovarian follicle involve keratinocyte and hepatocyte growth factor production by thecal cells and their action on granulosa cells. Endocrinology 1994; 135(2): 569-75.
[http://dx.doi.org/10.1210/endo.135.2.8033804] [PMID: 8033804]
[14]
Parrott JA, Skinner MK. Developmental and hormonal regulation of hepatocyte growth factor expression and action in the bovine ovarian follicle. Biol Reprod 1998; 59(3): 553-60.
[http://dx.doi.org/10.1095/biolreprod59.3.553] [PMID: 9716553]
[15]
Zachow RJ, Weitsman SR, Magoffin DA. Hepatocyte growth factor regulates ovarian theca-interstitial cell differentiation and androgen production. Endocrinology 1997; 138(2): 691-7.
[http://dx.doi.org/10.1210/endo.138.2.4950] [PMID: 9026427]
[16]
Guglielmo MC, Ricci G, Catizone A, et al. The effect of hepatocyte growth factor on the initial stages of mouse follicle development. J Cell Physiol 2011; 226(2): 520-9.
[http://dx.doi.org/10.1002/jcp.22361] [PMID: 20683913]
[17]
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): 291-9.
[http://dx.doi.org/10.1530/rep.1.00989] [PMID: 16885537]
[18]
Erickson GF, Shimasaki S. The physiology of folliculogenesis: the role of novel growth factors. Fertil Steril 2001; 76(5): 943-9.
[http://dx.doi.org/10.1016/S0015-0282(01)02859-X] [PMID: 11704115]
[19]
McGee EA, Hsueh AJW. Initial and cyclic recruitment of ovarian follicles. Endocr Rev 2000; 21(2): 200-14.
[http://dx.doi.org/10.1210/edrv.21.2.0394] [PMID: 10782364]
[20]
Parrott JA, Skinner MK. Kit-ligand/stem cell factor induces primordial follicle development and initiates folliculogenesis. Endocrinology 1999; 140(9): 4262-71.
[http://dx.doi.org/10.1210/endo.140.9.6994] [PMID: 10465300]
[21]
Hutt KJ, McLaughlin EA, Holland MK. KIT/KIT ligand in mammalian oogenesis and folliculogenesis: roles in rabbit and murine ovarian follicle activation and oocyte growth. Biol Reprod 2006; 75(3): 421-33.
[http://dx.doi.org/10.1095/biolreprod.106.051516] [PMID: 16790689]
[22]
Taniguchi F, Harada T, Deura I, Iwabe T, Tsukihara S, Terakawa N. Hepatocyte growth factor promotes cell proliferation and inhibits progesterone secretion via PKA and MAPK pathways in a human granulosa cell line. Mol Reprod Dev 2004; 68(3): 335-44.
[http://dx.doi.org/10.1002/mrd.20076] [PMID: 15112327]
[23]
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): 454-9.
[http://dx.doi.org/10.1095/biolreprod67.2.454] [PMID: 12135881]
[24]
Hillier SG, Whitelaw PF, Smyth CD. Follicular oestrogen synthesis: The ‘two-cell, two-gonadotrophin’ model revisited. Mol Cell Endocrinol 1994; 100(1-2): 51-4.
[http://dx.doi.org/10.1016/0303-7207(94)90278-X] [PMID: 8056158]
[25]
Oduwole OO, Huhtaniemi IT, Misrahi M. The roles of luteinizing hormone, follicle-stimulating hormone and testosterone in spermatogenesis and folliculogenesis revisited. Int J Mol Sci 2021; 22(23): 12735.
[http://dx.doi.org/10.3390/ijms222312735] [PMID: 34884539]
[26]
Patel S, Zhou C, Rattan S, Flaws JA. Effects of endocrine-disrupting chemicals on the ovary. Biol Reprod 2015; 93(1): 20.
[http://dx.doi.org/10.1095/biolreprod.115.130336] [PMID: 26063868]
[27]
Chou CH, Chen MJ. The effect of steroid hormones on ovarian follicle development. Vitam Horm 2018; 107: 155-75.
[http://dx.doi.org/10.1016/bs.vh.2018.01.013] [PMID: 29544629]
[28]
Zachow RJ, Ramski BE, Lee H. Modulation of estrogen production and 17beta-hydroxysteroid dehydrogenase-type 1, cytochrome P450 aromatase, c-met, and protein kinase Balpha messenger ribonucleic acid content in rat ovarian granulosa cells by hepatocyte growth factor and follicle-stimulating hormone. Biol Reprod 2000; 62(6): 1851-7.
[http://dx.doi.org/10.1095/biolreprod62.6.1851] [PMID: 10819792]
[29]
Osuga Y, Tsutsumi O, Momoeda M, et al. Evidence for the presence of hepatocyte growth factor expression in human ovarian follicles. Mol Hum Reprod 1999; 5(8): 703-7.
[http://dx.doi.org/10.1093/molehr/5.8.703] [PMID: 10421795]
[30]
Liu Y, Lin L, Zarnegar R. Modulation of hepatocyte growth factor gene expression by estrogen in mouse ovary. Mol Cell Endocrinol 1994; 104(2): 173-81.
[http://dx.doi.org/10.1016/0303-7207(94)90120-1] [PMID: 7988745]
[31]
Şahin N, Toylu A, Gülekli B, Doğan E, Kovali M, Atabey N. The levels of hepatocyte growth factor in serum and follicular fluid and the expression of c-Met in granulosa cells in patients with polycystic ovary syndrome. Fertil Steril 2013; 99(1): 264-269.e3.
[http://dx.doi.org/10.1016/j.fertnstert.2012.08.059] [PMID: 23036804]
[32]
Mäkelä JA, Koskenniemi JJ, Virtanen HE, Toppari J. Testis development. Endocr Rev 2019; 40(4): 857-905.
[http://dx.doi.org/10.1210/er.2018-00140] [PMID: 30590466]
[33]
Zirkin BR, Papadopoulos V. Leydig cells: Formation, function, and regulation. Biol Reprod 2018; 99(1): 101-11.
[http://dx.doi.org/10.1093/biolre/ioy059] [PMID: 29566165]
[34]
Thumfart KM, Mansuy IM. What are Sertoli cells? Historical, methodological, and functional aspects. Andrology 2023; 11(5): 849-59.
[http://dx.doi.org/10.1111/andr.13386] [PMID: 36651593]
[35]
Zhou R, Wu J, Liu B, et al. The roles and mechanisms of Leydig cells and myoid cells in regulating spermatogenesis. Cell Mol Life Sci 2019; 76(14): 2681-95.
[http://dx.doi.org/10.1007/s00018-019-03101-9] [PMID: 30980107]
[36]
Ricci G, Catizone A, Galdieri M. Pleiotropic activity of hepatocyte growth factor during embryonic mouse testis development. Mech Dev 2002; 118(1-2): 19-28.
[http://dx.doi.org/10.1016/S0925-4773(02)00247-2] [PMID: 12351166]
[37]
Ricci G, Guglielmo MC, Caruso M, et al. Hepatocyte growth factor is a mouse fetal Leydig cell terminal differentiation factor. Biol Reprod 2012; 87(6): 146.
[http://dx.doi.org/10.1095/biolreprod.112.104638] [PMID: 23077169]
[38]
Catizone A, Ricci G, Galdieri M. Expression and functional role of hepatocyte growth factor receptor (C-MET) during postnatal rat testis development. Endocrinology 2001; 142(5): 1828-34.
[http://dx.doi.org/10.1210/endo.142.5.8172] [PMID: 11316747]
[39]
Catizone A, Ricci G, Galdieri M. HGF and postnatal testis development. Mol Cell Endocrinol 2005; 241(1-2): 32-40.
[http://dx.doi.org/10.1016/j.mce.2005.04.010] [PMID: 15963637]
[40]
Del Bravo J, Catizone A, Ricci G, Galdieri M. Hepatocyte growth factor-modulated rat Leydig cell functions. J Androl 2007; 28(6): 866-74.
[http://dx.doi.org/10.2164/jandrol.107.002865] [PMID: 17609297]
[41]
Catizone A, Ricci G, Caruso M, et al. HGF modulates actin cytoskeleton remodeling and contraction in testicular myoid cells. Biomedicines 2015; 3(1): 89-109.
[http://dx.doi.org/10.3390/biomedicines3010089] [PMID: 28536401]
[42]
Luaces JP, Toro-Urrego N, Otero-Losada M, Capani F. What do we know about blood-testis barrier? current understanding of its structure and physiology. Front Cell Dev Biol 2023; 11: 1114769.
[http://dx.doi.org/10.3389/fcell.2023.1114769] [PMID: 37397257]
[43]
Catizone A, Ricci G, Caruso M, Ferranti F, Canipari R, Galdieri M. Hepatocyte growth factor (HGF) regulates blood–testis barrier (BTB) in adult rats. Mol Cell Endocrinol 2012; 348(1): 135-46.
[http://dx.doi.org/10.1016/j.mce.2011.07.050] [PMID: 21843593]
[44]
Catizone A, Ricci G, Bravo J, Galdieri M. Hepatocyte growth factor modulates in vitro survival and proliferation of germ cells during postnatal testis development. J Endocrinol 2006; 189(1): 137-46.
[http://dx.doi.org/10.1677/joe.1.06528] [PMID: 16614388]
[45]
Sullivan R, Mieusset R. The human epididymis: Its function in sperm maturation. Hum Reprod Update 2016; 22(5): 574-87.
[http://dx.doi.org/10.1093/humupd/dmw015] [PMID: 27307387]
[46]
Catizone A, Ricci G, Galdieri M. Functional role of hepatocyte growth factor receptor during sperm maturation. J Androl 2002; 23(6): 911-8.
[http://dx.doi.org/10.1002/j.1939-4640.2002.tb02349.x] [PMID: 12399538]
[47]
Uehara Y, Minowa O, Mori C, et al. Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature 1995; 373(6516): 702-5.
[http://dx.doi.org/10.1038/373702a0] [PMID: 7854453]
[48]
Bladt F, Riethmacher D, Isenmann S, Aguzzi A, Birchmeier C. Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud. Nature 1995; 376(6543): 768-71.
[http://dx.doi.org/10.1038/376768a0] [PMID: 7651534]
[49]
Webber L, Davies M, Anderson R, et al. ESHRE Guideline: Management of women with premature ovarian insufficiency. Hum Reprod 2016; 31(5): 926-37.
[http://dx.doi.org/10.1093/humrep/dew027] [PMID: 27008889]
[50]
Jiao W, Mi X, Qin Y, Zhao S. Stem cell transplantation improves ovarian function through paracrine mechanisms. Curr Gene Ther 2020; 20(5): 347-55.
[http://dx.doi.org/10.2174/1566523220666200928142333] [PMID: 32988352]
[51]
Levy O, Kuai R, Siren EMJ, et al. Shattering barriers toward clinically meaningful MSC therapies. Sci Adv 2020; 6(30): eaba6884.
[http://dx.doi.org/10.1126/sciadv.aba6884] [PMID: 32832666]
[52]
Zaher W, Harkness L, Jafari A, Kassem M. An update of human mesenchymal stem cell biology and their clinical uses. Arch Toxicol 2014; 88(5): 1069-82.
[http://dx.doi.org/10.1007/s00204-014-1232-8] [PMID: 24691703]
[53]
Jiao W, Mi X, Yang Y, et al. Mesenchymal stem cells combined with autocrosslinked hyaluronic acid improve mouse ovarian function by activating the PI3K-AKT pathway in a paracrine manner. Stem Cell Res Ther 2022; 13(1): 49.
[http://dx.doi.org/10.1186/s13287-022-02724-3] [PMID: 35109928]
[54]
Mi X, Jiao W, Yang Y, Qin Y, Chen ZJ, Zhao S. HGF secreted by mesenchymal stromal cells promotes primordial follicle activation by increasing the activity of the PI3K-AKT signaling pathway. Stem Cell Rev Rep 2022; 18(5): 1834-50.
[http://dx.doi.org/10.1007/s12015-022-10335-x] [PMID: 35089464]
[55]
Chen J, Jia Z, Zhang F, et al. HGF-modified human umbilical cord mesenchymal stem cells rescue impaired ovarian reserve function in chemotherapy-induced POI rats by improving angiogenesis while decreasing apoptosis and fibrosis in the ovary. Tissue Cell 2023; 82: 102121.
[http://dx.doi.org/10.1016/j.tice.2023.102121] [PMID: 37285749]
[56]
Wang DH, Ren J, Zhou CJ, Han Z, Wang L, Liang CG. Supplementation with CTGF, SDF1, NGF, and HGF promotes ovine in vitro oocyte maturation and early embryo development. Domest Anim Endocrinol 2018; 65: 38-48.
[http://dx.doi.org/10.1016/j.domaniend.2018.05.003] [PMID: 29890304]
[57]
Goda K, Fujisawa M, Shirakawa T, et al. Adenoviral-mediated HGF expression inhibits germ cell apoptosis in rats with cryptorchidism. J Gene Med 2004; 6(8): 869-76.
[http://dx.doi.org/10.1002/jgm.585] [PMID: 15293345]
[58]
Wiltshire EJ, Flaherty SP, Couper RTL. Hepatocyte growth factor in human semen and its association with semen parameters. Hum Reprod 2000; 15(7): 1525-8.
[http://dx.doi.org/10.1093/humrep/15.7.1525] [PMID: 10875860]
[59]
Kitamura M, Matsumiya K, Nishimura K, Yamanaka M, Okuyama A, Matsumoto K. Effect of hepatocyte growth factor on sperm motility. Am J Reprod Immunol 2000; 44(4): 193-6.
[http://dx.doi.org/10.1111/j.8755-8920.2000.440401.x] [PMID: 11076089]
[60]
Zhou X, He QH. Hepatocyte growth factor and male reproduction. Zhonghua Nan Ke Xue 2015; 21(8): 747-52.
[http://dx.doi.org/10.13263/j.cnki.nja.2015.08.016] [PMID: 26442306]
[61]
Cui S, Guo L, Li X, et al. Clinical safety and preliminary efficacy of plasmid pudk-hgf expressing human hepatocyte growth factor (HGF) in patients with critical limb ischemia. Eur J Vasc Endovasc Surg 2015; 50(4): 494-501.
[http://dx.doi.org/10.1016/j.ejvs.2015.05.007] [PMID: 26122834]
[62]
Nagoshi N, Tsuji O, Kitamura K, et al. Phase I/II study of intrathecal administration of recombinant human hepatocyte growth factor in patients with acute spinal cord injury: A double-blind, randomized clinical trial of safety and efficacy. J Neurotrauma 2020; 37(15): 1752-8.
[http://dx.doi.org/10.1089/neu.2019.6854] [PMID: 32323609]
[63]
Meng H, Chen B, Tao Z, et al. Safety and efficacy of adenovirus carrying hepatocyte growth factor gene by percutaneous endocardial injection for treating post-infarct heart failure: A phase iia clinical trial. Curr Gene Ther 2018; 18(2): 125-30.
[http://dx.doi.org/10.2174/1566523218666180404162209] [PMID: 29618307]
[64]
Ido A, Moriuchi A, Numata M, et al. Safety and pharmacokinetics of recombinant human hepatocyte growth factor (rh-HGF) in patients with fulminant hepatitis: A phase I/II clinical trial, following preclinical studies to ensure safety. J Transl Med 2011; 9(1): 55.
[http://dx.doi.org/10.1186/1479-5876-9-55] [PMID: 21548996]
[65]
Liu WW, Chen JY, Yu W, et al. Hepatocyte growth factor combined with autologous bone marrow mesenchymal stem cell transplantation for treatment of silicosis. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 2011; 29(1): 39-43.
[PMID: 21619796]

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