Progressive Reliance On Epithelial Plasticity Governs Lung Development, Homeostasis, And Regeneration

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Doctor of Philosophy (PhD)
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Cell & Molecular Biology
alveolar development
Hippo signaling
Cell Biology
Developmental Biology
Molecular Biology
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Penkala, Ian

Formation of the architecturally complex gas exchange surface of the lung during development requires precise temporal and spatial control of alveolar epithelial differentiation. Interference in this process can result in bronchopulmonary dysplasia, a devastating disease predominantly affecting premature infants. Despite our understanding of proximal airway developmental hierarchies, the distal alveolar lineage relationships and mechanisms of specification are unclear. Lung development is thought to proceed by stepwise lineage specification and differentiation of multipotent progenitors, beginning with specification of the lung endoderm and ending with differentiation and maturation of the alveolar epithelial type 1 (AT1) and type 2 (AT2) cells. AT1 cells are large, squamous cells that form the gas exchange surface, while AT2 cells are small, cuboidal, secretory cells which produce surfactant to maintain alveolar integrity. Consequently, these two lineages also have distinct programs of gene expression. In this dissertation I define the timing of prenatal specification of AT1 and AT2 cells using multiple lineage tracing tools and clonal analysis. Additionally, using a similar approach, I describe the different responses of AT1 and AT2 cells to neonatal and adult acute lung injury. In particular, I demonstrate both the robust plasticity of AT1 cells versus the relative quiescence of AT2 cells during neonatal injury as well as the dramatic reversal of this cellular plasticity during adult lung injury. These results suggest a developmental stage dependent response to acute lung injury. Finally, I demonstrate that YAP/TAZ actively maintain AT1 cell identity throughout the lifespan by preventing reprogramming into AT2 cells. Altogether this work provides a comprehensive analysis of the development and plasticity of the alveolar epithelium, identifying critical mechanisms required to maintain AT1 cell fate.

Edward E. Morrisey
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