Inflammatory Signals Induce AT2 Cell-Derived Damage-Associated Transient Progenitors that Mediate Alveolar Regeneration

• Published in: Cell stem cell Vol. 27; no. 3; pp. 366 - 382.e7
• Main Authors: Choi, Jinwook, Park, Jong-Eun, Tsagkogeorga, Georgia, Yanagita, Motoko, Koo, Bon-Kyoung, Han, Namshik, Lee, Joo-Hyeon
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.09.2020; Cell Press
• Subjects: Alveolar Epithelial Cells; Cell Differentiation; damage-associated transient progenitors; IL-1R1 and IL-1β; inflammation; lineage differentiation; Lung; lung stem cells; regeneration; Signal Transduction; stem cell fate; stem cell niche; Stem Cells; lineage differentiation; IL-1R1 and IL-1β; stem cell niche; stem cell fate; regeneration; inflammation; damage-associated transient progenitors; lung stem cells
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2020.06.020

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 stepwise mapping to cell fate transitions shows how an inflammatory niche controls alveolar regeneration by controlling stem cell fate and behavior. [Display omitted] •Injury-induced IL-1β signaling promotes differentiation of AT2 cells into AT1 cells•AT2 cells differentiate into AT1 cells via cell states of primed AT2 and DATPs•HIF1α signaling controls AT2-DAPT conversion and is essential for AT1 differentiation•Chronic inflammation impairs maturation of AT1 cells Choi et al. show that inflammatory signals play a crucial role during alveolar regeneration after injury. They define stepwise differentiation trajectories for AT2 cells into AT1 cells via damage-associated transient progenitors (DATPs) and find that unresolved inflammation stalls transition of DATPs into mature AT1 cells.