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FOXL2 and NR5A1 induce human fibroblasts into steroidogenic ovarian granulosa‐like cells
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FOXL2 and NR5A1 induce human fibroblasts into steroidogenic ovarian granulosa‐like cells
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Journal Article
FOXL2 and NR5A1 induce human fibroblasts into steroidogenic ovarian granulosa‐like cells
2024
Overview
Human granulosa cells in different stages are essential for maintaining normal ovarian function, and granulosa cell defect is the main cause of ovarian dysfunction. To address this problem, it is necessary to induce functional granulosa cells at different stages in vitro. In this study, we established a reprogramming method to induce early‐ and late‐stage granulosa cells with different steroidogenic abilities. We used an AMH‐fluorescence‐reporter system to screen candidate factors for cellular reprogramming and generated human induced granulosa‐like cells (hiGC) by overexpressing FOXL2 and NR5A1. AMH‐EGFP+ hiGC resembled human cumulus cells in transcriptome profiling and secreted high levels of oestrogen and progesterone, similar to late‐stage granulosa cells at antral or preovulatory stage. Moreover, we identified CD55 as a cell surface marker that can be used to isolate early‐stage granulosa cells. CD55+ AMH‐EGFP‐ hiGC secreted high levels of oestrogen but low levels of progesterone, and their transcriptome profiles were more similar to early‐stage granulosa cells. More importantly, CD55+ hiGC transplantation alleviated polycystic ovary syndrome (PCOS) in a mouse model. Therefore, hiGC provides a cellular model to study the developmental program of human granulosa cells and has potential to treat PCOS. Overexpression of FOXL2 and NR5A1 reprogrammed human fibroblast cells into late‐stage and early‐stage granulosa cells respectively. AMH‐EGFP+ hiGCs secret high levels of estradiol and progesterone, and CD55+ hiGCs secret high level of estradiol. CD55+ hiGC transplantation can alleviate DHEA‐induced PCOS and has potential for cell therapy of PCOS.
Publisher
John Wiley & Sons, Inc,John Wiley and Sons Inc
Subject
/ Cells
/ Female
/ Females
/ Forkhead Box Protein L2 - genetics
/ Forkhead Box Protein L2 - metabolism
/ Genes
/ Granulosa Cells - metabolism
/ Humans
/ Mice
/ Original
/ Ovaries
/ Polycystic Ovary Syndrome - metabolism
/ Polycystic Ovary Syndrome - pathology
/ Steroidogenic Factor 1 - genetics
