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Reprod Sci. 2018 May;25(5):712-726. doi: 10.1177/1933719117725814. Epub 2017 Aug 31.

An Embryonic and Induced Pluripotent Stem Cell Model for Ovarian Granulosa Cell Development and Steroidogenesis.

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1 Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology and Reproductive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
2 Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
3 Computational Methods Development, Cancer Genome Analysis, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
4 Victor Chang Cardiac Research Institute, University of New South Wales, Sydney, New South Wales, Australia.
5 Canary Center at Stanford for Early Cancer Detection, Stanford School of Medicine, Palo Alto, CA, USA.
6 Affiliated Faculty, Harvard Stem Cell Institute, Cambridge, MA, USA. Gerami-Naini is now with the Department of Diagnostic Sciences, School of Dental Medicine, Tufts University, Boston MA, USA. Eaton is now with the Division of Reproductive Endocrinology and Fertility, Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, NC, USA. O'Connell is now with the Intellia Therapeutics, Inc, Cambridge, MA, USA. Kiezun is now with the , Boston, MA, USA.


Embryoid bodies (EBs) can serve as a system for evaluating pluripotency, cellular differentiation, and tissue morphogenesis. In this study, we use EBs derived from mouse embryonic stem cells (mESCs) and human amniocyte-derived induced pluripotent stem cells (hAdiPSCs) as a model for ovarian granulosa cell (GC) development and steroidogenic cell commitment. We demonstrated that spontaneously differentiated murine EBs (mEBs) and human EBs (hEBs) displayed ovarian GC markers, such as aromatase (CYP19A1), FOXL2, AMHR2, FSHR, and GJA1. Comparative microarray analysis identified both shared and unique gene expression between mEBs and the maturing mouse ovary. Gene sets related to gonadogenesis, lipid metabolism, and ovarian development were significantly overrepresented in EBs. Of the 29 genes, 15 that were differentially regulated in steroidogenic mEBs displayed temporal expression changes between embryonic, postnatal, and mature ovarian tissues by polymerase chain reaction. Importantly, both mEBs and hEBs were capable of gonadotropin-responsive estradiol (E2) synthesis in vitro (217-759 pg/mL). Live fluorescence-activated cell sorting-sorted AMHR2+ granulosa-like cells from mEBs continued to produce E2 after purification (15.3 pg/mL) and secreted significantly more E2 than AMHR2- cells (8.6 pg/mL, P < .05). We conclude that spontaneously differentiated EBs of both mESC and hAdiPSC origin can serve as a biologically relevant model for ovarian GC differentiation and steroidogenic cell commitment. These cells should be further investigated for therapeutic uses, such as stem cell-based hormone replacement therapy and in vitro maturation of oocytes.


embryonic stem cells; iPSC; native hormones; ovarian tissue regeneration; steroidogenesis

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