Origins of neonatal lung myofibroblasts

PROJECT SUMMARY The lung mesenchyme consists of heterogeneous cell types that are critical for lung development, architecture, and maintaining homeostasis in the mature organ. Alveoli mature during the final days of gestation and early postnatal life through a process called alveologenesis, which involves secondary septation—morphological changes in alveoli that create additional septa and increase the surface area for gas exchange. Postnatally, myofibroblasts rapidly expand and contract the lung tissue, facilitating secondary septation. However, the mechanisms regulating myofibroblast development, expansion, and transient existence remain poorly understood. In this proposal, we will leverage a novel murine model targeting neonatal alveolar myofibroblasts to test the hypothesis that these cells are specified by a morphogen gradient of bone morphogenetic protein (BMP) signaling in the embryonic lung. This signaling drives their clonal expansion in the postnatal lung, followed by the activation of intrinsic apoptotic pathways that lead to their decline after alveologenesis. Our specific aims for this proposal are (1) to utilize a novel lineage reporter mouse for alveolar myofibroblasts to study their expansion and activation of apoptotic pathways; (2) to investigate how the divergence of airway and alveolar myofibroblasts occurs around the embryonic endoderm in a BMP-dependent manner; and (3) to determine the necessity and sufficiency of alveolar myofibroblasts in driving secondary septation following neonatal lung injury. These studies will provide new insights into myofibroblast plasticity, molecular drivers of myofibroblast dynamics, and identify pathways that could enhance alveolar septation.