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

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. 25-day-old female ICR mice were purchased from Liaoning Changsheng Biotechnology Co., Ltd and housed under controlled conditions (12-hour light/dark cycle, temperature 22 ± 2°C) with free access to food and water. DHEA was dissolved in 10% sesame oil (in 95% ethanol) and administered daily to each mouse in the model group at 6 mg/100 g body weight in 0.1 mL for 20 days. Control mice were injected with vehicle in the same way.