Jason Rock, PhD

Core

Proximal airways of mouse and human lungs are lined by a pseudostratified epithelium. We have shown that TRP63+ basal cells of these airways function as a population of stem cells capable of long-term self-renewal and the generation of differentiated daughters (multi-ciliated and secretory cells). Using a combination of in vivo mouse models and in vitro studies with human cells, we showed that the evolutionarily conserved Notch pathway is required for the differentiation of basal stem cells, particularly along secretory (mucous cell) lineages, but is not required for their self-renewal. Bronchioles (more distal airways with smaller diameters) in mice are lined by a simple columnar epithelium made up of multi-ciliated cells and secretory cells (but lack basal cells). Here, evidence suggests that secretory cells (that express Scgb1a1) are stem cells capable of long-term self-renewal and differentiation. Importantly, we currently do not know whether a similar "zone" exists in the human lung; most human airways, right down to the broncho-alveolar duct junction (BADJ), are lined by a pseudostratified epithelium that contains TRP63+ basal stem cells. The alveoli are made up of Type I and Type 2 alveolar epithelial cells (AEC1 and AEC2, respectively). For decades, AEC2 have been regarded as the alveolar epithelial stem cell, but there were no rigorous in vivo genetic lineage tracing data to support this claim. Recently, we showed that AEC2 do give rise to AEC1 under steady state conditions and that the kinetics of this process are enhanced in response to bleomycin-induced lung injury. Importantly, our data (and data from the laboratories of our collaborators Hal Chapman, UCSF and Brigid Hogan, Duke University) support a model in which there is another, non-AEC2 alveolar epithelial stem cell. We are currently using the technique of genetic lineage tracing in mice to test the progenitor potential of putative stem cell populations in vivo during lung development, in adults under steady state conditions, and in response to a variety of lung injuries. We combine gene expression analysis with in vivo and in vitro gain- and loss-of-function experiments to test hypotheses about the mechanisms that regulate the self-renewal and differentiation of stem cells from mouse and human lungs. Our goal is to translate this information into genetic, molecular and cell-based therapies for lung disease.

Pulmonary fibrosis is a progressive and debilitating lung disease in which the alveolar gas exchange region of the lung is replaced by scar tissue. At least three populations have been proposed as the source of mesenchymal cells (i.e., myofibroblasts) that produce the characteristic fibrotic lesions: (1) epithelial cells, through the process of epithelial-to-mesenchymal transition, (2) circulating fibrocytes and (3) resident stromal cells, including fibroblasts, pericytes and "contractile interstitial cells." We recently combined genetic lineage tracing in the mouse model of bleomycin-induced pulmonary fibrosis with high-resolution confocal microscopic analysis of healthy and fibrotic human lungs to investigate the cellular origins of pulmonary fibrosis. Our data suggest that AEC2 cells and multiple stromal cell types, including CSPG4/NG2+ pericytes and PDGFRA+ "fibroblasts," proliferate in fibrotic lungs. However, neither AEC2 nor pericytes are a source of myofibroblasts. We are interested in identifying subsets of resident stromal populations in healthy lungs and understanding their developmental origins and how they contribute, directly or indirectly, to the progression of lung disease.