CRISPR/Cas9-mediated activation of NR5A1 steers female human embryonic stem cell-derived bipotential gonadal-like cells towards a steroidogenic cell fate.

Autor: Danti L; Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, 00290, Finland., Lundin K; Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, 00290, Finland., Sepponen K; Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, 00290, Finland., Yohannes DA; Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, 00290, Finland.; Research Programs Unit, Translational Immunology & Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, 00290, Finland., Kere J; Folkhälsan Research Centre, Stem Cells and Metabolism Research Program, University of Helsinki, Helsinki, 00290, Finland.; Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, 14183, Sweden., Tuuri T; Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, 00290, Finland., Tapanainen JS; Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, 00290, Finland. juha.tapanainen@helsinki.fi.; Department of Obstetrics and Gynecology, HFR - Cantonal Hospital of Fribourg and University of Fribourg, Fribourg, 1708, Switzerland. juha.tapanainen@helsinki.fi.
Jazyk: angličtina
Zdroj: Journal of ovarian research [J Ovarian Res] 2023 Sep 20; Vol. 16 (1), pp. 194. Date of Electronic Publication: 2023 Sep 20.
DOI: 10.1186/s13048-023-01264-5
Abstrakt: The nuclear receptor subfamily 5 group A member 1 (NR5A1), encoding steroidogenic factor 1 (SF-1), has been identified as a critical factor in gonadal development in animal studies. A previous study of ours suggested that upregulation of NR5A1 during early gonadal differentiation in male (46,XY) human pluripotent stem cells steers the cells into a more mature gonadal cell type. However, the detailed role of NR5A1 in female gonadal differentiation has yet to be determined. In this study, by combining the processes of gonadal differentiation and conditional gene activation, we show that NR5A1 induction predominantly upregulates the female gonadal marker inhibin subunit α (INHA) and steroidogenic markers steroidogenic acute regulatory protein (STAR), cytochrome P450 family 11 subfamily A member 1 (CYP11A1), cytochrome P450 family 17 subfamily A member 1 (CYP17A1), hydroxy-delta-5-steroid dehydrogenase (HSD3B2) and hydroxysteroid 17-beta dehydrogenase 1 (HSD17B1). In contrast, NR5A1 induction did not seem to affect the bipotential gonadal markers gata binding protein 4 (GATA4) and Wilms' tumour suppressor 1 (WT1) nor the female gonadal markers r-spondin 1 (RSPO1) and wnt family member 4 (WNT4). Differentially expressed genes were highly associated with adrenal and ovarian steroidogenesis pathways. Moreover, time-series analysis revealed different dynamic changes between male and female induced samples, where continuously upregulated genes in female gonadal differentiation were mostly associated with adrenal steroidogenesis. Thus, in contrast to male gonadal differentiation, NR5A1 is necessary but not sufficient to steer human embryonic stem cell (hESC)-derived bipotential gonadal-like cells towards a more mature somatic, female cell fate. Instead, it seems to direct bipotential gonadal-like cells more towards a steroidogenic-like cell population. The information obtained in this study helps in elucidating the role of NR5A1 in gonadal differentiation of a female stem cell line.
(© 2023. BioMed Central Ltd., part of Springer Nature.)
Databáze: MEDLINE
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