UCSF

Until recently, adult lung regeneration has been a poorly defined phenomena in mammals. Publications from the 1970s demonstrated in small mammals the ability for tissue to expand, through a process called alveologenesis, post-pneumonectomy. Only recently have the molecular processes involved in adult alveologenesis begun to be defined. Using methods of non-pathologic lung injury and lineage tracing analysis, we demonstrate that the alveolar epithelial type II cells (AECII) are the predominant, proliferative epithelial cell population that contribute to formation of new alveolar epithelium. We also show that pneumonectomy induces proliferation in AECIIs in-vitro and in-vivo, and that two separate molecular pathways, Notch and Wnt, are seemingly necessary for both the proliferation and differentiation phase of AECIIs into AECIs during adult alveologenesis. For the first time, we have strongly suggestive evidence that non-human primate lungs are capable of adult alveologenesis, and that the AECII cell is the predominant proliferative cell type as well. These findings further support the potential for adult alveologenesis in humans and define a cell type of interest to pursue. In a separate study, we looked to better define heterogeneity within an adult lipofibroblast progenitor cell population. Initially, we used a cell transplantation technique after bleomycin injury to show that the PDGFR-A+ lipofibroblast cell can integrate themselves into areas of fibrosis in the lung. We then performed single-cell sequencing to demonstrate cell heterogeneity within this lipofibroblast population. This analysis led us to the TCF21 gene, a gene which has been associated with lung branching morphogenesis and also the cell of origin for cardiac myofibroblasts. Again, using lineage tracing techniques, we demonstrated that TCF21 cells are capable of differentiating in to pulmonary myofibroblasts in the context of bleomycin injury.