Project description:Premature birth disrupts normal lung development and places infants at risk for bronchopulmonary dysplasia (BPD), a disease increasing in incidence which disrupts lung health throughout the lifespan. The TGFβ superfamily has been implicated in BPD pathogenesis, however, what cell lineage it impacts remains unclear. We show that the primary TGFβ receptor, Tgfbr2, is critical for AT1 cell fate maintenance and function. Loss of Tgfbr2 in AT1 cells during late lung development leads to AT1-AT2 cell reprogramming and altered pulmonary architecture, which persists into adulthood. Restriction of fetal lung stretch and associated AT1 cell spreading through a model of oligohydramnios enhances AT1-AT2 reprogramming. Transcriptomic and proteomic analysis reveal that expression of extracellular matrix components by AT1 cells is attenuated with loss of Tgfbr2. Cell spreading assays shows that TGFβ signaling regulates integrin transcription to alter AT1 cell morphology, which further impacts ECM expression through changes in mechanotransduction. These data reveal the cell intrinsic necessity of TGFβ signaling to maintain AT1 fate and define this cell lineage as a major orchestrator of the alveolar matrisome, which, if altered, may predispose to BPD.
Project description:This experiment profiled the transcriptomes of developing AT1 and AT2 cells from the beginning of embryonic alveolar development through the end of alveologenesis at 6 weeks of age.
Project description:Acetyl-CoA critically participates in post-translational modification of proteins, central carbon and lipid metabolism in several compartments of eukaryotic cells. In mammals, the acetyl-CoA transporter 1 (AT1) facilitates the flux of cytosolic acetyl-CoA into the endoplasmic reticulum (ER) enabling the acetylation of proteins of the secretory pathway in concert with dedicated acetyltransferases including Nat8. Homologues of AT1 and Nat8 were identified in the apicomplexan parasites Toxoplasma gondii and Plasmodium berghei. However, the implication of acetyl-CoA pool influx into the ER in acetylation of ER-transiting proteins and their relevance throughout the parasites’ life cycle is unknown. Here, we report proteome-wide analyses, which revealed unprecedented widespread N-terminal acetylation marks of secreted proteins in both parasites. Deletion of the gene coding for AT1 in both parasites, resulted in global loss of fitness and in addition to retardation in erythrocytic development, malaria parasites are blocked in transmission to mosquitoes. However, in absence of AT1 proteome wide lysine and N-terminal acetylation modifications remain unaltered. This highlights a role of AT1 in parasite development uncoupled to acetylation capacity, indicative of an unusually active acetylation machinery occurring in the ER of Apicomplexa.
Project description:Hypercapnia has deleterious effects on cell function, including inhibition of alveolar epithelial cells (AEC) and fibroblast proliferation without causing cell death. Classical studies and lineage-trace models demonstrated that surfactant-producing AT2 cells can serve as stem cells for the structurally and functionally distinct alveolar type 1 cells (AT1) This AT2 reprogramming depends on Wnt/βcat signaling, a pathway that plays critical roles in tissue development and homeostasis throughout the organism lifespan. We found that high CO2 inhibits AT2 cell proliferation and self renewal, and promote their differentiation to ATEC and AT1 cells
Project description:The goal of this study was to compare wildtype adult lung epithelium to epithelium from Cdc42 AT1-KO mice and mice after left bronchial ligation model.
