CRC Therapy Identifies Indian Hedgehog Signaling in Mouse Endometrial Epithelial Cells and Inhibition of Ihh-KLF9 as a Novel Strategy for Treating IUA.

ABSTRACT

Intrauterine adhesion (IUA) causes menstrual disturbance and infertility. There is no effective treatment available for moderate to severe IUA cases. Stem cell-based therapy has been investigated for treating IUA but is limited in clinical applications due to issues including the precise induction of differentiation, tumorigenesis, and unclear molecular mechanisms. In our recent study, we isolated and expanded the long-term cultures of conditional reprogrammed (CR) mouse endometrial epithelial cells. Treating IUA mice with these CR cells (CRCs) restored the morphology and structure of the endometrium and significantly improved the pregnancy rate. In this study, our data with high-throughput sequencing, CRISPR knockout Ihh-/-CRCs, and transplantation identified for the first time that the Indian hedgehog (Ihh) gene plays a critical role in the regulation of endometrial epithelial cell proliferation. We also found that aberrant activated Ihh-krüppel-like factor 9 (KLF9) signaling contributes to the inhibition of normal progesterone receptor (PR) function in IUA mice. Thus, we hypothesized that inhibition of the Ihh-KLF9 pathway may be a novel strategy to treat IUA. Our data demonstrated that treatment with the hedgehog signaling inhibitor Vismodegib restored the morphology, structure, and microenvironment of the endometrium, and greatly improved the pregnancy rate in IUA mice. This study suggests a promising application of hedgehog inhibitors as a targeted drug in the IUA clinic.