In the lung and many other tissues the transition from organogenesis to tissue homeostasis in adulthood is associated with a dramatic decrease in the rate of cell proliferation. Despite this, the capacity to replenish specialized lung cell types is retained through long-term maintenance of progenitor cells that can replace cells lost due to normal turnover and injury. Progenitor cells typically vary in their potency; their capacity for long-term maintenance/self-renewal and their differentiation potential. We are interested in defining functionally distinct progenitor cell pools that maintain the lung epithelium and how the proliferative capacity and differentiation potential of these cells is regulated in normal and disease states.

Previous work in other laboratories has demonstrated that nonciliated Clara cells of bronchiolar airways function as an abundant pool of facultative progenitor cells. However, unlike obligate progenitor cells of rapidly renewing tissues such as the gut, Clara cells only proliferate infrequently in the normal lung and fulfill other specialized functions when in their quiescent state. In this capacity Clara cells are more analogous to other facultative progenitor cells such as beta cells of the endocrine pancreas and hepatocytes of the liver. We have used naphthalene-induced lung injury, a model of Clara cell ablation that exploits their unique capacity to bioactivate lipophilic pollutants, to reveal mechanisms of repair that are independent of this abundant facultative progenitor cell pool. Rare naphthalene-resistant regenerative cells with properties of tissue stem cells localize to discrete microenvironments in airways and generate a nascent epithelium composed of both Clara and ciliated cells (See References for more details). Our ongoing studies are aimed at understanding molecular signals that regulate the behavior of airway progenitor cell types and further functional analysis of these cells in vivo, in vitro and following transplantation.