Julia Holden
Pronouns: She/Her
Research Mentor(s): Fatima Fattahi
Research Mentor School/College/Department: Department of Internal Medicine, Division of Pulmonary & Critical Care Medicine / Medicine
Program: UROPF
Session: Session 2 (10:00am – 10:50am)
Authors: Julia Holden, Fatima Fattahi, Patrick Mclinden, Natalie Walker, Vibha Lama
Abstract
Lung transplantation has the lowest 10-year survival rate of any solid organ transplant necessitating better understanding of the mechanisms that contribute to this issue. The primary cells responsible for lung fibrosis (scar tissue formation) that occurs over the course of chronically rejecting lungs are mesenchymal cells (MCs)–particularly along bronchovascular bundles–collections of small airways and blood vessels. Methods: In order to better understand these cells and their contribution to chronic lung allograft dysfunction (CLAD), we digested sections of autopsy-derived human lung tissue from normal and chronically rejected lungs and isolated MCs through a selective cell culture approach. RNA and protein isolation was performed, and subsequent RT-PCR and western blot analysis was conducted in order to compare Normal- and CLAD-MCs. Flow cytometric sorting of primary mouse lung cells was done to isolate distinct populations for downstream mRNA analysis to verify primary human lung MC gene expression results. Immunohistochemistry was utilized to correlate in vitro data with in situ observations. Results: We found higher collagen I mRNA expression in MCs isolated from CLAD lungs which was verified by western blot analysis. Sorted mouse lung cell populations confirmed this finding in a mouse model of CLAD. In order to better characterize these cells, we also identified other markers of these cells isolated from bronchovascular bundles (BVBs). In particular, we contend that these cells are PDGFRa+/COL1A1+/GLI1+/FOXF1+/ITGA8-, and that these cells are the primary contributors to the fibrosis observed in chronically rejecting human and mouse lungs along bronchovascular bundles. Conclusions: The purpose of our research was to better characterize the cells of the bronchovascular bundle in hopes of later discovering possible points of intervention for the overproduction of collagen I in chronically rejecting lungs. As rates of transplant survival are extremely low, treatments are deeply important and meaningful to those receiving life-saving lung transplants.
