(189) The Transcription Factor Runx1 in Endometrial Stromal Cells regulates the Maturation of Uterine Natural Killer Cells, influencing Decidual Angiogenesis and Vascular Remodeling.

Abstract Authors: Purba Mukherjee1, Athilakshmi Kannan², Indrani C. Bagchi², and Milan K. Bagchi¹
1. Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL
2. Department of Comparative Biosciences, University of Illinois Urbana-Champaign, Urbana, IL

Abstract Text: One notable adaptation at the maternal-fetal interface of species with hemochorial placentation, such as human and mouse, is the remarkable vascular expansion and remodeling that occur in the maternal stromal compartment as it undergoes extensive differentiation, known as decidualization, during pregnancy establishment. There is ample evidence that uterine natural killer (uNK) cells, which accumulate in the mesometrial decidua following implantation, are involved in the remodeling of uterine blood vessels associated with pregnancy. The mechanism by which uNK cells regulate adaptive responses in the decidua remains unclear, primarily due to the lack of appropriate animal models. To address this issue, we have developed a mouse model called Runx1^d/d. In this model, the conditional deletion of the transcription factor Runx1 in uterine stromal cells results in significant subfertility. This condition is characterized by defects in the formation of the uterine endothelial network and a failure to modify the spiral arteries during gestation. In our examination of the uNK cell population in the decidua of Runx1^d/d mice, we observed that the number of DBA lectin-reactive uNK cells was approximately twice as high in these mutant mice compared to the control Runx1^f/f decidua. While uNK cells typically cease proliferation by day 12 of gestation in normal decidua, those in the Runx1^d/d decidua continued to proliferate. Histological analyses revealed that the proliferating uNK cells were smaller, less granular, and appeared immature compared to the non-proliferating, larger, granular uNK cells found in the Runx1^f/f decidua. We propose the idea that the abnormal homing, maturation, and signaling of uNK cells in the Runx1^d/d decidua contribute to the defects in endothelial cell function observed in these mutant mice. We are currently investigating this hypothesis by exploring the underlying transcriptome of the uNK cells in the Runx1^d/d mice. We performed single-nuclei RNA sequencing on decidual and placental tissues from day 13 of gestation in these mice. Differential gene expression and gene ontology analysis of our data indicate that several pro-angiogenesis-related genes are downregulated in uNK cells present in the Runx1^d/d decidua. These findings support the concept that, in these mutant mice, the uNK cells are unable to express and secrete key paracrine regulators needed to act on endothelial cells to influence maternal vascular remodeling during early pregnancy.
This work was supported by the Eunice Kennedy Shriver NICHD/NIH R01 HD090066 and R21 HD109726 (to ICB and MKB).