Metabolism of Epithelial Progenitor Cells
During lung injury, the pulmonary epithelium is often the site of injury where cells are damaged and lost. The repair process initiates proliferation of epithelial progenitor cells followed by differentiation of those cells into terminal states allowing for the restoration of homeostasis. The plasticity of the epithelial progenitors, along with some cell states that have long been thought of as terminal states, is an area of active investigation within the context of chronic diseases. This plasticity appears to be impaired under certain stress conditions, including those caused by genetic mutations seen in patients with lung diseases. Of the many stresses in the lung, aging is a biological process that impairs this progenitor function while also altering the fundamental molecular processes that regulate the homeostatic state of the epithelial cell. Within this context, we are very interested in asking what aging does to promote the loss of epithelial plasticity and can that be targeted therapeutically to promote normal repair in disease. One potential hypothesis supported by previous observations made by our group is that age-associated changes to metabolism alter the balance of critical metabolites such as lactate, leading to a state that no longer favors differentiation. We are currently applying our transgenic mouse models and complex in-vitro culture systems to untangle the relationship between altered metabolism, aging, and progenitor capacity during lung injury.
Inflammatory Fibroblasts in Lung Injury
The heterogeneity and diversity of pulmonary cell populations found after injury has been well documented with the introduction and accessibility of single cell sequencing. We are now aware of a population of fibroblasts named “inflammatory fibroblasts” that emerges early in the injury process and expresses cytokines. The emergence of these cells and their function is not well understood. Though we know that inflammation is a critical aspect of normal tissue repair, over activation and persistence of inflammation can promote a pathological state. Furthermore, the inflammatory fibroblasts can persist after the peak of an initial inflammatory wave in an acute injury. We are very interested in understanding what role these cells play in injury and disease. Do these cells interact with immune cells alone? Or perhaps are they involved in regulation of the epithelial or endothelial compartments? Our goal is to explore this biology across multiple injuries to better understand the signaling mechanisms and pathwaths of the niches populated by these inflammatory fibroblasts.