Intrinsic and extrinsic factors controlling the development of human lung macrophages

Human tissue-macrophages demonstrate diverse functions and distinct transcriptomic profiles across organs. They are imprinted by the local tissue environment and contribute to the tissue development, homeostasis, and regeneration. The embryonic macrophages begin to infiltrate the human lung as early as seven post conception weeks (pcw). However, the mechanisms that govern lung macrophage specification and their contribution to human lung development remain poorly understood. This project aims to dissect the cell-intrinsic gene regulatory networks (GRNs), spatial distribution patterns, and signaling pathways regulating the interactions of macrophages and the human developing lung (7–22 pcw). These aims will be achieved by combining single-cell multiomic analysis, high-resolution microscopy, and signaling perturbation using novel 3D tissue models. First, this project will determine the GRNs controlling the identity of fetal lung macrophages by employing multiomic analysis tools. Second, the spatial-temporal maps of macrophages in the fetal lung will be generated using high-resolution light sheet fluorescence microscopy to investigate the distribution patterns and specific cellular niche(s). Lastly, this study will establish novel complex lung tissue models to investigate the underlying mechanisms regulating lung-macrophage interactions. These complementary techniques will expand our knowledge of human tissue macrophage specification and functions, providing insights to the field of both lung and macrophage biology.