Rachel L. Zemans Lab

Several acute and chronic lung diseases result from ineffective regeneration of the alveolar epithelium after injury. We have no therapeutic options to promote regeneration, in part because of our limited understanding of the underlying mechanisms. The alveolar epithelium consists of type 1 and type 2 alveolar epithelial cells (AECs). AEC1s play a critical role in barrier function since they cover >95% of the alveolar surface and facilitate efficient gas exchange by virtue of their exquisitely thin morphology. However, AEC1s are highly susceptible to death during lung injury due to a variety of insults. Surviving AEC2s are the principal progenitor responsible for regenerating the injured alveolar epithelium. AEC2s proliferate to replace lost cells, then differentiate into AEC1s to restore normal alveolar architecture and function. Impaired regeneration results in lung disease, including pulmonary fibrosis. We have identified mechanisms underlying AEC2 proliferation, including β-catenin signaling (1) and AEC2-to-AEC1 differentiation, including a novel AEC2-AEC1 transitional cell state that emerges transiently during normal regeneration (2) but persists in pulmonary fibrosis (3). We also study the role of immune cells in causing lung injury and both promoting physiologic regeneration and impairing regeneration during disease pathogenesis. We hope these findings may eventually lead to novel therapies to promote normal regeneration and ameliorate lung disease.