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

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.

组织再生是由多种细胞层级与细胞状态介导的多步骤过程，这些细胞层级和状态同样与组织功能异常及发病机制密切相关。本研究借助单细胞RNA测序（single-cell RNA sequencing）结合体内谱系示踪与类器官模型，精准绘制了损伤修复与肺再生过程中肺泡谱系细胞的动态轨迹。我们鉴定出一类独特的AT2谱系群体——损伤相关瞬时祖细胞（Damage-Associated Transient Progenitors，DATPs），该群体在肺泡再生过程中产生。我们发现，间质巨噬细胞来源的IL-1β通过HIF1α介导的糖酵解通路，将表达Il1r1的部分AT2细胞预激活为DATPs，而该通路是成熟AT1细胞分化所必需的。尤为关键的是，IL-1β介导的慢性炎症会阻断AT1细胞的分化过程，导致DATPs异常累积并削弱肺泡再生能力。综上，这套针对细胞命运转变的分步图谱揭示了炎症微环境如何通过调控干细胞的命运与行为，损害肺泡再生过程。