Stem cells undergo dynamic changes in response to injury to regenerate lost cells. However, the identity of transitional states and the mechanisms that drive their trajectories remain understudied. Using lung organoids, multiple in vivo repair models, single-cell transcriptomics and lineage tracing, we find that alveolar type-2 epithelial cells undergoing differentiation into type-1 cells acquire pre-alveolar type-1 transitional cell state (PATS) en route to terminal maturation. Transitional cells undergo extensive stretching during differentiation, making them vulnerable to DNA damage. Cells in the PATS show an enrichment of TP53, TGFβ, DNA-damage-response signalling and cellular senescence. Gain and loss of function as well as genomic binding assays revealed a direct transcriptional control of PATS by TP53 signalling. Notably, accumulation of PATS-like cells in human fibrotic lungs was observed, suggesting persistence of the transitional state in fibrosis. Our study thus implicates a transient state associated with senescence in normal epithelial tissue repair and its abnormal persistence in disease conditions.

干细胞因损伤而发生动态变化，以再生丢失的细胞。然而，过渡国家的身份以及推动其发展轨迹的机制仍未得到充分研究。利用肺类器官、多种体内修复模型、单细胞转录组学和谱系追踪，我们发现正在分化为 1 型细胞的肺泡 2 型上皮细胞在分化为 1 型细胞的过程中获得前肺泡 1 型过渡细胞状态 (PATS)。终端成熟。移行细胞在分化过程中经历广泛的拉伸，使它们容易受到 DNA 损伤。PATS 中的细胞显示出 TP53、TGFβ、DNA 损伤反应信号传导和细胞衰老的富集。功能的获得和丧失以及基因组结合测定揭示了 TP53 信号传导对 PATS 的直接转录控制。值得注意的是，在人类纤维化肺中观察到 PATS 样细胞的积累，表明纤维化过渡状态的持续存在。因此，我们的研究暗示了与正常上皮组织修复中的衰老相关的短暂状态及其在疾病条件下的异常持续性。