Mesenchymal cell plasticity and signaling in lung regeneration

PROJECT SUMMARY Regeneration of the lung following severe injury is an imperfect process and frequently leads to permanently altered lung structure and dysplastic cell types. After severe injury, such as influenza or COVID-19, the alveolus can either regenerate in form and function (adaptive regeneration) or be replaced by airway-derived dysplastic epithelium (maladaptive repair). These maladaptive cells and structures do not participate in gas exchange and likely contribute to the long-term reduction in pulmonary function seen in some patients from severe lung injury, highlighting the need for the development of new therapeutics with which to promote functional adaptive alveolar regeneration. Developing these new therapies will require a comprehensive understanding of not only the progenitor cells and their functions after injury, but also how they signal and interact with other cells within the injured alveolar niche. The alveolus is composed of a fragile layer of epithelium surrounded by a dense network of mesenchymal cells which serve important roles in paracrine signaling within the alveolar niche. Recent work from our lab and others has demonstrated the heterogeneity of these cells, identifying two key populations of alveolar mesenchyme, those that express Pdgfra (alpha+) and those that express Pdgfrb (beta+). Based on my extensive preliminary data demonstrating a key role of alpha+ cell proliferation, plasticity, and Notch signaling in alveolar regeneration after viral injury in both mouse and human lungs, I will test the hypothesize that specific mesenchymal cell lineages that arise from injury-induced plasticity establish and maintain the maladaptive epithelial regenerative response, in part through Notch mesenchymal-epithelial signaling. In Aim 1 of this proposal, I will examine how alpha+ cell proliferation and plasticity are defined and maintained after viral injury. The proposed research in Aim 1 will further develop my skills in transcriptomic and epigenomic analyses and physiological impacts of injury on lung function. In the independent phase outlined in Aim 2, I will define the importance of Notch mediated mesenchymal paracrine signaling within the alveolar niche during adaptive vs maladaptive regeneration. My primary mentor, Dr. Edward Morrisey is an internationally renowned lung biologist who has identified many key cell types and pathways which drive regeneration of the injured lung. I have also assembled a diverse advisory committee of experts in bioinformatics, epigenetics, physiologic readouts of recovery of lung function after injury, and Notch signaling who will assist me in training of these areas. The proposed work will be conducted at the University of Pennsylvania, where I will benefit from the rich intellectual environment, wide-ranging resources, collaborative scientific community in pulmonary and mesenchymal biology, and the full support of the institution. Together, this proposal outlines a rigorous research and training plan that will establish the foundation to advance my career in lung and mesenchymal cell biology.