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ORCID

http://orcid.org/0000-0003-2265-3355

Date of Award

Spring 5-15-2020

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Developmental, Regenerative, & Stem Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

The lung is a respiratory organ capable of facilitating gas exchange between external atmospheric O2 and internal CO2 in the bloodstream, necessary to oxygenate tissues. Alveoli, small balloon shaped structures at the distal end of the respiratory tree, are the meeting point between air and blood where gas exchange occurs through simple diffusion. Generation of functionally mature alveoli occurs during alveologenesis, the final postnatal stage of lung development in mice. During alveologenesis the surface area of the lung increases through formation of septal ridges (septation) which are extracellular matrix rich invaginations of the nascent alveolar wall that subdivide the alveoli. Alveolar myofibroblasts (AMFs) are interstitial contractile cells that are thought to generate the septal ridges through deposition of elastin. AMFs are abundant during alveologenesis but are absent in the adult through an undetermined process. Disruptions to alveologenesis lead to an insufficiency of alveoli, characteristic of the pediatric disease of bronochpulmonary dysplasia (BPD), a major cause of preterm infant morbidity and chronic lung disease. Fibroblast growth factors (FGFs), a family of cell signaling molecules important for development, have been implicated in directing alveologenesis with Fgfr3-/-; Fgfr4-/- double knockout animals having alveolar simplification, a characteristic histological finding in BPD patients. Fgf18 has been suggested as a ligand signaling to FGFR3/4 but Fgf18-/- knockout mice die at birth precluding studies into its function postnatally. In this study we generated a floxed allele of Fgf18 (Fgf18f) that allows for the investigation of Fgf18 function postnatally and a CreERT2 knockin allele (Fgf18CreERT2) that allows the identification of cells that express Fgf18 and their lineage. We found that Fgf18CreERT2 marks AMFs during alveologenesis. Lineage tracing of AMFs into the adult revealed loss of the AMF lineage from the alveolus, potentially through a phagocytic process mediated by multiple immune populations. Using the Fgf18f allele paired with a ubiquitous inducible CreERT2 driver line (CAGG-CreERT2), ablation of Fgf18 resulted in alveolar simplification during alveologenesis, similar to Fgfr3-/-; Fgfr4-/- mice. Removal of Fgf18 exclusively in cells expressing Fgf18CreERT2 (Fgf18CreERT2/f) resulted in alveolar simplification manifesting only in adult animals, suggesting a role for Fgf18 in alveolar maturation after the first phase of alveologenesis has ended. Fgf18CreERT2/f animals also developed signs of pulmonary hypertension, a common co-occurrence in patients with BPD. Taken together these studies demonstrate that the AMF lineage is depleted at the conclusion of alveologenesis and that Fgf18 is required for normal postnatal lung development.

Language

English (en)

Chair and Committee

David Ornitz

Committee Members

Steven Brody, Benjamin Humphreys, Kristen Kroll, Robert Mecham,

Available for download on Wednesday, May 15, 2120

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