James Witkowski
Research Mentor: Rachel Zemans
Mentor Department: Internal Medicine, Medicine
Author(s): Christopher Ting, Rachel Zemans, Jessica Liang, Xulun Zhang, Kendall Foster, Qinxue Shen, Zie Craig, Anuradha Basyal, Haichun Pan, James Witkowski, Joshua Franzen
Session: Session 6 (3:00 PM – 3:50 PM)
Presentation Type: Poster 136
Abstract
Pulmonary fibrosis is a progressive lung disease characterized by scarring of the lungs that hinders gas exchange and leads to gradual deterioration of lung function. In healthy lungs, epithelial stem cells can be mobilized to repair the lungs after injury. However, in pulmonary fibrosis, this repair process is unsuccessful, leading to the appearance of abnormal epithelial cell states, such as KRT17+/KRT5- aberrant basaloid cells. Aberrant basaloid cells accumulate in diseased fibrotic lungs, but their origin remains unknown. Identifying the cells from which aberrant basaloid cells originate from can inform the development of clinical therapeutics targeting these cells to prevent or reverse fibrosis. We performed in vivo lineage tracing using SftpcCreERT2;mTmG and Rtkn2CreER;tdTomato mice injured with bleomycin and butylated hydroxytoluene (BHT) and stained for marker genes of alveolar type II (AT2) cells, alveolar type 1 (AT1) cells, club cells, KRT8HI transitional cells, and aberrant basaloid cells. Our data suggests that aberrant basaloid cells may emerge from AT2s after BHT (~70% of aberrant basaloid cells are lineage-labeled) but they did not appear to make KRT5+ basal cells. Similarly, AT2s did not appear to make basal cells after bleomycin injury. We administered multiple doses of bleomycin to induce chronic, non-resolving fibrosis and discovered that the majority of KRT17+ cells were KRT5+ basal cells, which resembles the human disease where aberrant basaloid cells are a minority among lung epithelial cells. AT1s did not appear to make transitional nor AT2s after bleomycin injury. They also did not appear to proliferate after injury, making them an unlikely source of aberrant basaloid cells.
