Spatial transcriptomics reveals tanscriptional perturbations leading to uterine squamous metaplasia, atrophy, and infertility in a mouse model of RTHa
This study identifies an unknown role for KLF9 signaling in normal uterine development, which is decreased in a mouse model of resistance to thyroid hormone (RTHa), resulting in infertility through ectopic IL-33 expression produced by abnormally differentiated, KLF9-deficient endometrial cells. Utilizing a combination of genetically engineered mouse models, histopathology, spatial transcriptomics, and pharmacological inhibitors, we revealed that infertility in RTHa results from abnormal endometrial differentiation mediated by KLF9 suppression. These abnormally differentiated endometrial cells were the source of ectopic IL-33 overexpression. Increased endometrial IL-33 led to T-cell infiltration, destruction of glands, and endometrial fibrosis, which culminated in infertility. This study uncovers a link between TRa1 and KLF9 signaling for normal endometrial differentiation, reveals a mechanism for ectopic uterine IL-33 in female fertility, and provides new insights on the impact of hypothyroidism in female reproduction. Overall design: A total of 190 regions of interest (ROI) were taken from 13 mouse uterus sections (6 Thra1 PV/+ and 7 wild-type mice), which included endometrial mucosa, glands, and stroma; a minimum of 5 ROIs were taken per category per mouse.