Functional tissue regeneration is required for the restoration of normal organ homeostasis after severe injury. Some organs, such as the intestine, harbour active stem cells throughout homeostasis and regeneration; more quiescent organs, such as the lung, often contain facultative progenitor cells that are recruited after injury to participate in regeneration. Here we show that a Wnt-responsive alveolar epithelial progenitor (AEP) lineage within the alveolar type 2 cell population acts as a major facultative progenitor cell in the distal lung. AEPs are a stable lineage during alveolar homeostasis but expand rapidly to regenerate a large proportion of the alveolar epithelium after acute lung injury. AEPs exhibit a distinct transcriptome, epigenome and functional phenotype and respond specifically to Wnt and Fgf signalling. In contrast to other proposed lung progenitor cells, human AEPs can be directly isolated by expression of the conserved cell surface marker TM4SF1, and act as functional human alveolar epithelial progenitor cells in 3D organoids. Our results identify the AEP lineage as an evolutionarily conserved alveolar progenitor that represents a new target for human lung regeneration strategies.

中文翻译：

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通过进化上保守的上皮祖细胞再生肺泡

功能组织再生是严重损伤后正常器官稳态恢复所必需的。一些器官，例如肠道，在整个体内平衡和再生过程中都含有活跃的干细胞；更静止的器官，如肺，通常含有兼性祖细胞，这些祖细胞在受伤后被募集以参与再生。在这里，我们展示了 2 型肺泡细胞群中的 Wnt 反应性肺泡上皮祖细胞 (AEP) 谱系作为远端肺中的主要兼性祖细胞。AEPs 在肺泡稳态期间是一个稳定的谱系，但在急性肺损伤后迅速扩张以再生大部分肺泡上皮。AEP 表现出独特的转录组、表观基因组和功能表型，并对 Wnt 和 Fgf 信号传导做出特异性反应。与其他提出的肺祖细胞相比，人类 AEP 可以通过表达保守的细胞表面标记 TM4SF1 直接分离，并在 3D 类器官中充当功能性人类肺泡上皮祖细胞。我们的结果将 AEP 谱系确定为进化上保守的肺泡祖细胞，代表了人类肺再生策略的新目标。