Dissertations and Theses (Open Access)

Date of Graduation

8-2026

Document Type

Dissertation (PhD)

Program Affiliation

Genetics and Epigenetics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Jichao Chen

Committee Member

Tingting Mills

Committee Member

Pamela Wenzel

Committee Member

George Eisenhoffer

Committee Member

Don Gibbons

Committee Member

Richard Behringer

Abstract

Lung mesenchymal cells are a heterogeneous group of cells that remodel the extracellular matrix, support the repair of the air-blood barrier, and instruct the differentiation of neighboring lineages. Despite their importance, the 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 remain unclear. 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 myofibroblasts, in which a fraction reprogrammed into a proximal subpopulation, the ductal myofibroblasts (DMFs). Apoptotic clearance proved dispensable for normal alveolar maturation. Instead, it acts as a preventive mechanism, eliminating cells that otherwise become pathogenically contractile and deposit extracellular matrix during an allergic response. In a house-dust-mite model of allergic asthma, persistent reprogrammed cells reactivated the contractile program, 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 whose inhibition effects are imperceptible under homeostasis but potentially pathogenic under inflammatory challenge, defining the alveolar mesenchyme as an active participant in airway disease.

Keywords

Lung fibroblasts, asthma, fibrosis, myofibroblasts, lung development

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Available for download on Thursday, February 04, 2027

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