Pathogenesis of Airway Stem Cell Abnormalities in Obliterative Bronchiolitis

University Of Iowa, Iowa City IA

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Abstract

Project Summary Lung transplantation has become the standard of care for end-stage lung diseases with no available medical therapy. However, long-term survival after lung transplantation is affected by development of chronic lung allograft dysfunction (CLAD), which is progressively fatal and for which there is no effective therapy. Almost 50% of recipients die within five years due to the development of obliterative bronchiolitis (OB) in the allograft, an obstructive type of CLAD. We developed a novel orthotopic lung transplant model in the ferret that closely models human CLAD. Utilizing this model, we showed for the first time that airway submucosal glands (SMGs), a facultative airway stem cell niche, and basal stem cells (BSCs) are depleted in human and ferret OB allografts. We also showed that in human and ferret OB allografts, there is a predominance of Keratin 14 (Krt14) positive BSCs and a loss of Keratin 15 (Krt15) BSCs. This loss of Krt15 in BSCs decreases their proliferative capacity. Additionally, with our collaborator (Dr. Wa Xian), we demonstrated a dominance of pro-fibrotic and pro- inflammatory BSC clones in end-stage lung diseases like chronic obstructive pulmonary disorder, idiopathic pulmonary fibrosis, and cystic fibrosis. We and other investigators have shown that glandular myoepithelial cells (MECs) are a facultative stem cell niche that repairs airway injury and contributes to surface airway BSC and differentiated epithelial cells. The role of these glandular MECs in the transplanted lung remains unclear. Since the bronchial SMG SC niche is not conserved in widely used rodent models, there has been a critical gap in our ability to study and understand how alterations in the bronchial SMG SC niche contribute to impaired epithelial regeneration in the allograft and lead to CLAD. To address, we generated novel ACTA2-CreERT2:ROSA-TG ferrets to lineage label MECs. The overall objective of this proposal is to understand mechanisms leading to CLAD pathogenesis, identify BSC signatures for early detection of CLAD, and identify potential therapeutic targets promoting CLAD. We hypothesize that tight regulation of region-specific airway surface epithelium and SMGs is disrupted in transplanted lungs, which promotes suboptimal regeneration resulting in the expansion of abnormal surface BSCs, the depletion of stem cells in the SMGs, and thus the exacerbation of inflammatory responses that drive CLAD. We will achieve these objectives by addressing the following specific aims: 1) Determine the multipotency of glandular MECs to regenerate surface BSC with abnormal stem cell properties in CLAD. 2) Identify how Keratin 14/15 interact with Stratifin (Sfn) to modulate p63 levels and direct BSC fates. 3) Determine the effect of persistent Krt14 expression coupled with the loss of Krt15 and the emergence of inflammatory basal cell clones on the development of OB in human allografts. The expected outcomes will provide an understanding of the mechanisms leading to the development of CLAD, and identify novel ways to detect, prevent/treat CLAD.