Investigating the role of mesenchymal R-Spondin2 during human lung development

项目摘要

PROJECT ABSTRACT Mammalian respiratory system development is regulated by complex reciprocal signaling events that take place between the epithelial cells lining the airways and the surrounding mesenchymal cells. Despite the lung mesenchyme being home to cell types that provide crucial signals during development, the identity and function of specific cell types in the lung mesenchyme are poorly defined, especially in the context of human development. To interrogate mesenchymal cell heterogeneity in the developing human lung, our lab has conducted single cell RNA sequencing on multiple human lung samples spanning 8-22 weeks of gestation. Using cell-clustering approaches, we identified a mesenchymal cell population highly enriched for expression of the WNT agonist R-Spondin2 (RSPO2). Strikingly, mutations in this gene cause severe lung aplasia in humans. My co-fluorescent in situ hybridization (FISH) and immunofluorescence (IF) data from human lung tissue sections show that RSPO2 is expressed adjacent to proliferating distal epithelial progenitor cells and that the RSPO2 receptor, LGR5, is expressed almost exclusively in the epithelial progenitor cells. These data suggest that RSPO2+ mesenchymal cells may have a critical role in regulating epithelial progenitor cells during human lung development. The goals of this proposal are to: 1) interrogate mesenchymal cell heterogeneity and function in the context of epithelial progenitor cell regulation in the developing human lung and 2) explain a functional role for RSPO2+ mesenchymal cells during human lung development.