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.

组织再生是一个由不同细胞层次和状态介导的多步骤过程，这些层次和状态也与组织功能障碍和发病机制有关。在这里，我们利用单细胞 RNA 测序结合体内谱系追踪和类器官模型来精细绘制损伤修复和肺再生过程中肺泡谱系细胞的轨迹。我们鉴定了肺泡再生过程中出现的一个独特的 AT2 谱系群体，即损伤相关瞬时祖细胞 (DATP)。我们发现，间质巨噬细胞衍生的 IL-1β 会引发表达Il1r1的 AT2 细胞子集，通过HIF1α介导的糖酵解途径转化为 DATP ，这是成熟 AT1 细胞分化所必需的。重要的是，IL-1β介导的慢性炎症会阻止 AT1 分化，导致 DATP 异常积累并损害肺泡再生。总之，这种细胞命运转变的逐步映射显示了炎症生态位如何通过控制干细胞的命运和行为来控制肺泡再生。