title: Induction of estrogen-sensitive epithelial cells derived from human-induced pluripotent stem cells to repair ovarian function in a chemotherapy-induced mouse model of premature ovarian failure.
abstract: The incidence of premature ovarian failure (POF), a condition causing amenorrhea and hypergonadotropic hypoestrogenism in women before the age of 40, has been increasing in recent years. As an irreversible pathological change, improved treatment strategies for this disease are urgently needed. In this study, a type of microRNA (miR-17-3p) was used to guide the differentiation of human-induced pluripotent stem (iPS) cells into hormone-sensitive ovarian epithelial (OSE)-like cells in vitro. To prevent their morphological transformation into fibroblast-like cells, MiR-17-3p, a microRNA that suppresses vimentin expression, was transfected into human iPS cells. Subsequently, these cells were successfully induced into OSE-like cells in vitro after treatment with estrogen and cell growth factors. Compared with controls, iPS cells transfected with miR-17-3p expressed higher levels of epithelial markers (cytokeratin 7, AE1, AE3, and E-cadherin) and estrogen receptors (ERα and ERβ) while levels of mesenchymal markers (fibronectin, vimentin, and N-cadherin) lowered after the induction. The human iPS cell-derived OSE-like cells were then injected into cyclophosphamide-induced POF model mice to determine their potential benefit as grafts to repair ovarian tissues. The OSE-like cells survived within POF mouse ovaries for at least 14 days in vivo. Compared with the negative controls, expressions of cytokeratin 7 and ERβ proteins were elevated while fibronectin and vimentin levels in ovarian tissues were downregulated in the OSE-like cell transplantation group. Moreover, the ovarian weight and plasma E2 level increased over time in the transplantation with OSE-like cells, compared with control groups. Hence, we can draw the conclusion that iPS cells can be induced to differentiate into OSE-like cells in vitro.
authors.affiliation: 1 Shanghai Geriatric Institute of Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine , Shanghai, China .
authors.forename: Te
authors.initials: T
authors.lastname: Liu
authors.forename: Wenxing
authors.initials: W
authors.lastname: Qin
authors.forename: Yongyi
authors.initials: Y
authors.lastname: Huang
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jiejun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D051379:Mice; D009929:Organ Size; D016133:Polymerase Chain Reaction; D016649:Primary Ovarian Insufficiency / Q000139:chemically induced / Q000628:therapy
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha
references.citation: Acta Biochim Biophys Sin (Shanghai). 2012 Mar;44(3):197-206
references.pmid: 22285730
references.citation: Ann N Y Acad Sci. 2008;1135:138-45
references.pmid: 18574219
references.citation: J Mol Endocrinol. 2008 Jun;40(6):281-96
references.pmid: 18502821
references.citation: Stem Cells. 2009 Jun;27(6):1265-75
references.pmid: 19489092
references.citation: Oncogene. 2010 Apr 15;29(15):2302-8
references.pmid: 20190813
references.citation: J Clin Oncol. 2007 Aug 1;25(22):3198-204
references.pmid: 17664466
references.citation: J Clin Invest. 2010 Sep;120(9):3120-6
references.pmid: 20739754
references.citation: Histochem Cell Biol. 2009 May;131(5):553-63
references.pmid: 19224238
references.citation: Int J Mol Med. 2011 Sep;28(3):381-8
references.pmid: 21503569
references.citation: Bioessays. 2012 Jun;34(6):472-6
references.pmid: 22419173
references.citation: Cell Prolif. 2009 Jun;42(3):385-93
references.pmid: 19397591
references.citation: Oncogene. 2011 Aug 11;30(32):3522-36
references.pmid: 21423204
references.citation: Cell. 2009 Feb 6;136(3):411-9
references.pmid: 19203577
references.citation: Mol Med Rep. 2012 Sep;6(3):535-42
references.pmid: 22735917
references.citation: Hum Reprod. 2003 Oct;18(10):2031-8
references.pmid: 14507817
references.citation: Cell. 2006 Aug 25;126(4):663-76
references.pmid: 16904174
references.citation: Nat Biotechnol. 2009 Aug;27(8):743-5
references.pmid: 19590502
references.citation: Science. 2007 Dec 21;318(5858):1920-3
references.pmid: 18063756
references.citation: Sci Transl Med. 2011 May 11;3(82):82ra39
references.pmid: 21562231
references.citation: Aust N Z J Obstet Gynaecol. 2004 Feb;44(1):6-9
references.pmid: 15089860
references.citation: Breast Cancer Res Treat. 2012 Aug;134(3):1081-93
references.pmid: 22476851
references.citation: Stem Cells Dev. 2012 Aug 10;21(12):2322-32
references.pmid: 22264161
references.citation: Proc Natl Acad Sci U S A. 2009 Jan 20;106(3):808-13
references.pmid: 19139414
references.citation: Hum Reprod Update. 2005 Jul-Aug;11(4):391-410
references.pmid: 15919682
references.citation: Endocr Rev. 2001 Apr;22(2):255-88
references.pmid: 11294827
references.citation: Biol Reprod. 1993 Aug;49(2):221-7
references.pmid: 8373945
references.citation: J Mol Endocrinol. 2010 Nov;45(5):257-79
references.pmid: 20668067
references.citation: Med Hypotheses. 2012 Aug;79(2):197-201
references.pmid: 22595803
references.citation: J Clin Invest. 2010 Jan;120(1):51-9
references.pmid: 20051636
references.citation: Mol Cancer. 2011 Aug 18;10:99
references.pmid: 21851624
references.citation: Int J Mol Med. 2011 Mar;27(3):393-9
references.pmid: 21234519
references.citation: Fertil Steril. 2011 Apr;95(5):1595-600
references.pmid: 21256485
references.citation: J Biomed Biotechnol. 2011;2011:381928
references.pmid: 22187524
references.citation: Stem Cells Dev. 2009 Jan-Feb;18(1):137-49
references.pmid: 18605894
references.citation: Stem Cells. 2011 Aug;29(8):1206-18
references.pmid: 21678528
references.citation: Clin Exp Metastasis. 2009;26(8):965-79
references.pmid: 19771525
references.citation: Cell. 2007 Nov 30;131(5):861-72
references.pmid: 18035408
references.citation: Best Pract Res Clin Gastroenterol. 2012 Feb;26(1):35-45
references.pmid: 22482524
references.citation: FEBS J. 2012 Jun;279(11):2047-59
references.pmid: 22498306
references.citation: Mol Hum Reprod. 2010 Apr;16(4):241-50
references.pmid: 20086006
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5856-61
references.pmid: 18391196
references.citation: Int J Med Sci. 2012;9(7):592-602
references.pmid: 23028242
references.citation: Reprod Biol Endocrinol. 2003 Oct 07;1:70
references.pmid: 14609432