Spatial Transcriptomics Reveals Inhba/Smad2/E2f4 Axis in Lrp2high Thecal Cell Proliferation in Androgen-Induced PCOS Mice
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PROVIDER: PRJNA1260957 | ENA |
REPOSITORIES: ENA
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Project description: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.
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Project description:Polycystic Ovary Syndrome (PCOS) is a widespread reproductive disorder with hyperandrogenemia and impaired follicular development. Granulosa cells (GC) and thecal cells (TC) are crucial during follicular development, but their responses to androgen remain poorly understood at subpopulation levels. Using single-cell RNA sequencing and spatial transcriptomics, we analyzed GC and TC subpopulations in Dehydroepiandrosterone-induced PCOS-like mice to determine the ovarian microenvironment characters. We observed gene expression changes in steroidogenesis and cell-cell communications, with significant landscape shifts in subtypes. GC subsets showed an inflammatory GC5 expansion and loss of luteinized GC7, while TC subsets exhibited an increased TC2 population with enhanced lipid metabolism and androgen response. Intercellular signaling was heightened, particularly with amplified ligand-receptor interactions for Ptn-Ncl and Mdk-Ncl. Steroidogenesis was altered for PCOS's steroid hormone abnormalities. These findings revealed androgen impact in the cell subpopulations of follicular microenvironment and underscored the importance of Ptn-Ncl and Mdk-Ncl in PCOS-associated impaired follicular development.
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Project description:Polycystic ovary syndrome (PCOS), the most common cause of anovulatory infertility, is characterized by increased ovarian androgen production, arrested follicle development, and is frequently associated with insulin resistance. These PCOS phenotypes are associated with exaggerated ovarian responsiveness to FSH and increased pregnancy loss. To examine whether the perturbations in follicle growth and the intrafollicular environment affects development of the mature PCOS oocyte, genes that are differentially expressed in PCOS compared to normal oocytes were defined using microarray analysis. This analysis detected approximately 8000 transcripts. Hierarchical clustering and principal component analysis revealed differences in global gene expression profiles between normal and PCOS oocytes. 374 genes had a statistically-significant increase or decrease in mRNA abundance in PCOS oocytes. A subset of these genes was associated with chromosome alignment and segregation during mitosis and/or meiosis, suggesting that increased mRNAs for these proteins may negatively affect oocyte maturation and/or early embryonic development. Of the 374 differentially expressed genes, 68 contained putative androgen receptor, retinoic acid receptor, and/or peroxisome proliferating receptor gamma binding sites, including 9 of the genes involved in chromosome alignment and segregation. These analyses demonstrated that normal and PCOS oocytes that are morphologically indistinguishable and of high quality exhibit different gene expression profiles. Furthermore, altered mRNA levels in the PCOS oocyte may contribute to defects in meiosis and/or mitosis which might impair oocyte competence for early development and therefore contribute to poor pregnancy outcome in PCOS. Keywords: disease state analysis
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