Lung Allograft Stem Cell Regeneration and Immune Destruction

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PROJECT SUMMARY: End-stage lung disease is the third leading cause of death worldwide. Lung transplantation is often the only option for patients with advanced lung disease, yet 50% of recipients die within five years due to the development of chronic lung allograft dysfunction (CLAD). This project seeks to examine the basis for the loss of region-specific stem cells and impaired airway regeneration, with a long-term goal of improving cell-based regenerative medicine approaches. We will make use of innovative transgenic ferret models in our well-established orthotopic lung transplantation model. We will investigate the role of glandular myoepithelial cells (MECs) in renewing submucosal gland (SMG) cells and generating abnormal surface basal stem cells (BSCs) in CLAD. We hypothesize that sustained regenerative pressures drive MECs to exit their SMG stem cell niche to reconstitute surface BSCs with abnormal lineage properties that promote an immune response. Additionally, this project will determine the regenerative function of KRT7+ glandular duct cells (DCs) during the progression of CLAD. We hypothesize that the gland duct is a maturation point for MEC stem cells to adopt a surface BSCs phenotype that is bypassed under sustained regenerative stresses in CLAD. Finally, we will determine the relationship of antigen-experienced B-cells in promoting alloimmune and autoimmune reactions against airway stem cells to drive CLAD. We hypothesize that prolonged regeneration of surface BSCs by reserve MEC stem cells leads to the retention of MEC proteins on the airway surface. This ectopic expression of self-antigens promotes an autoimmune response against the SMG stem cells niche. Currently, end-stage lung disease is a significant cause of morbidity. However, we expect that by clarifying the processes that deplete stem cells in transplanted lungs, we will improve the likelihood of developing long-term objectives of developing effective stem cell therapies to sustain lung function and resilience to prevent CLAD.