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Spatial Transcriptomics Reveals Inhba/Smad2/E2f4 Axis in Lrp2high Thecal Cell Proliferation in Androgen-Induced PCOS Mice

ABSTRACT: Hyperandrogenemia is a primary character of polycystic ovary syndrome (PCOS), a leading cause of woman infertility. As a source of androgen secretion, thecal cells (TC) exhibit hyperplasia in the ovarian of PCOS conditions providing a potential mechanism for hyperandrogenemia. However, the molecular events driving TC hyperproliferation are not fully elucidated. In this study, we employed spatial transcriptomics investigating the ovarian of a mouse PCOS model induced by dehydroepiandrosterone (DHEA). Substantial alteration was observed in gene expression across multiple cell types in the ovarian, and a dramatic expansion was observed in Lrp2high subpopulation of TC. Functional analysis of gene interaction led to identification of the Inhba/Smad2/E2f4 pathway in the hyperproliferation of Lrp2high subset. Knockdown of any gene in the pathway led to suppression of TC proliferation, with a dominant impact upon Inhba inactivation. These results suggest that the Inhba/Smad2/E2f4 axis may be responsible for TC over proliferation in PCOS and a potential therapeutic target in the control of PCOS.

ORGANISM(S): Mus musculus

PROVIDER: GSE296728 | GEO | 2025/08/27

REPOSITORIES: GEO

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Project description:The molecular mechanisms that regulate the pivotal transformation processes observed in the follicular wall following the pre-ovulatory LH-surge, are still not established, particularly for cells of the thecal layer. To elucidate thecal and granulosa cell type-specific biological functions and signaling pathways, large dominant bovine follicles were collected before and 21 hrs after an exogenous GnRH induced LH surge. Because LH receptor density varies within the granulosa cell populations, antral granulosa (aGC; those aspirated by follicular puncture) and membrane associated granulosa (mGC; those scraped from the follicular wall) were compared to thecal cell expression profiles determined by mRNA microarrays. Thecal cell gene expression was less affected in the peri-ovulatory follicle when compared to granulosa cells, as evidenced by only 2% versus 25% of the ~11,000 genes expressed changing in response to the LH surge, respectively. The majority of the 203 LH-regulated thecal genes were also LH regulated in granulosa cells, leaving a total of 58 genes as LH-regulated theca cell specific genes. Most of the 58 genes (i.e., 74%) thecal specific genes including several known thecal markers (CYP17A1, NR5A1) were downregulated, while most genes identified are new to theca. Many of the newly identified upregulated thecal genes (e.g., PTX3, RND3, PPP4R4) were also upregulated in granulosa. Minimal expression differences were observed between aGC and mGC, however, transcripts encoding extracellular proteins (NID2) and matrix modulators (ADAMTS1, SASH1) predominated these differences. We also identified large numbers of unknown LH-regulated granulosa cell genes and discuss their putative roles in ovarian function. The single dominant ovarian follicle was collected from each cow before the LH surge or 22 hours after GnRH (used to induce LH surge). RNA was extracted from three independent cells within each follicle and there were hybridized on Affymetrix microarrays.

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Spatial Transcriptomics Reveals Inhba/Smad2/E2f4 Axis in Lrp2high Thecal Cell Proliferation in Androgen-Induced PCOS Mice

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