Project description:Alveolar epithelial cell fate decisions drive lung development and regeneration. Using transcriptomic and epigenetic profiling coupled with genetic mouse and organoid models, we identified Klf5 as a critical regulator of alveolar epithelial cell fate across the lifespan. During prenatal lung development and alveologenesis, Klf5 enforces alveolar epithelial type 1 (AT1) cell lineage fidelity. While it is dispensable for both adult AT1 and alveolar epithelial type 2 (AT2) cell homeostasis, Klf5 regulates AT2 cell plasticity after injury. Klf5 represses AT2 cell proliferation and enhances AT2-AT1 cell differentiation in a spatially restricted manner in both infectious and non-infectious models of acute respiratory distress syndrome. Moreover, ex vivo organoid assays reveal that Klf5 modulates AT2 cell fate decisions through reducing AT2 cell sensitivity to inflammatory signaling. These data highlight a major transcriptional regulator of AT1 cell lineage commitment and of the AT2 cell response to inflammatory crosstalk during lung regeneration.
Project description:The extent of lung regeneration following catastrophic damage and the potential role of adult stem cells in such a process remains obscure. Sublethal infection of mice with an H1N1 influenza virus related to that of the 1918 pandemic triggers massive airway damage followed by apparent regeneration. We show here that p63-expressing stem cells in the bronchiolar epithelium undergo rapid proliferation after infection and radiate to interbronchiolar regions of alveolar ablation. Once there, these cells assemble into discrete, Krt5+ pods and initiate expression of markers typical of alveoli. Gene expression profiles of these pods suggest that they are intermediates in the reconstitution of the alveolar-capillary network eradicated by viral infection. The dynamics of this p63-expressing stem cell in lung regeneration mirrors our parallel findings that defined pedigrees of human distal airway stem cells assemble alveoli-like structures in vitro and suggests new therapeutic avenues to acute and chronic airway disease. 3 colonies fron control and H1N1 influenza treated lungs (12 dpi) ,each were picked for whole genome microarray analysis
Project description:The role of nutrient signaling processes in the fate decision of CD8 is incompletely understood. By performing in vivo pooled CRISPR-Cas9 screening, we uncovered nutrient signaling processes underpinning the dynamics and heterogeneity of CD8 T cell fate decisions.
Project description:The role of nutrient signaling processes in the fate decision of CD8 are incompletely understood. By performing in vivo pooled CRISPR-Cas9 screening, we uncovered nutrient signaling processes underpinning the dynamics and heterogeneity of CD8 T cell fate decisions.
Project description:The role of nutrient signaling processes in the fate decision of CD8 is incompletely understood. By performing in vivo pooled CRISPR-Cas9 screening, we uncovered nutrient signaling processes underpinning the dynamics and heterogeneity of CD8 T cell fate decisions.
Project description:The role of nutrient signaling processes in the fate decision of CD8 is incompletely understood. By performing in vivo pooled CRISPR-Cas9 screening, we uncovered nutrient signaling processes underpinning the dynamics and heterogeneity of CD8 T cell fate decisions.
Project description:The role of nutrient signaling processes in the fate decision of CD8 T cells are incompletely understood. By performing in vivo pooled CRISPR-Cas9 screening, we uncovered nutrient signaling processes underpinning the dynamics and heterogeneity of CD8 T cell fate decisions.
Project description:Tissue regeneration is a multi-step process mediated by diverse cellular hierarchies and states that are also implicated in tissue dysfunction and pathogenesis. Here, we leveraged single-cell RNA sequencing in combination with in vivo lineage tracing and organoid models to finely map the trajectories of alveolar lineage cells during injury repair and lung regeneration. We identified a distinct AT2-lineage population, Damage-Associated Transient Progenitors (DATPs), that arises during alveolar regeneration. We found that interstitial macrophage-derived IL-1β primes a subset of AT2 cells expressing Il1r1 for conversion into DATPs via a HIF1α-mediated glycolysis pathway, which is required for mature AT1 cell differentiation. Importantly, chronic inflammation mediated by IL-1β prevents AT1 differentiation, leading to aberrant accumulation of DATPs and impaired alveolar regeneration. Together, this step-wise mapping to cell fate transitions shows how an inflammatory niche impairs alveolar regeneration by controlling stem cell fate and behavior.
