Lung Fibroblast Plasticity Revealed by a BCL2-Overexpression Mouse Model During Lung Development and Asthma

Maria Jose Gacha Garay (Advisor: Tingting Mills, PhD; Off-site Advisor: Jichao Chen, PhD)

          Lung mesenchymal cells are a heterogeneous group that remodels the extracellular matrix, supports the repair of the air-blood barrier, and instructs the differentiation of neighboring lineages. Despite their importance, functions, regulation, and fates of these subpopulations remain incompletely understood. This thesis addresses the pathophysiological role of alveolar myofibroblasts (AMFs), contractile cells in the distal lung that drive secondary septation during alveologenesis and whose dysregulation is associated with pulmonary diseases. Unlike other mesenchymal cells, AMFs are transient residents of the lung and are cleared by apoptosis upon completion of alveolar maturation. While AMF differentiation and proliferation are known to be essential for alveologenesis, the relevance of their apoptotic clearance and the consequences of AMF persistence for adult lung structure and function have not been established. Using a lineage-specific inducible mouse model expressing the pro-survival protein BCL2, we prevented AMF apoptosis without disrupting their developmental program. Persistent AMFs altered the organization of elastic fibers and the distribution and fate of distal-lung myofibroblasts, and a fraction reprogrammed into a proximal subpopulation, the ductal myofibroblasts (DMFs). In a house-dust-mite model of allergic asthma, persistent DMF-like cells reactivated the contractile program (ACTA2, SM22), and the lungs showed increased airway resistance, elastance, and tissue damping. Single-cell profiling further revealed that distinct mesenchymal subpopulations contribute to asthma pathogenesis through different programs. Together, these findings reframe AMF apoptosis as a developmental sculpting mechanism that is proven to be dispensable for normal alveolar maturation and acts as a preventive mechanism, eliminating cells that, when retained, otherwise become pathogenically contractile and ECM-depositing during allergic response.

Advisory Committee:

• Tingting Mills, PhD, Chair
• Jichao Chen, PhD, Co-Chair
• Richard Behringer, PhD
• George Eisenhoffer, PhD
• Don Gibbons, MD, PhD
• Pamela Wenzel, PhD

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