Alveolar regeneration through a Krt8+transitional stem cell state that persists in human lung fibrosis
Alveolar regeneration through a Krt8+transitional stem cell state that persists in human lung fibrosis
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DOI：
10.1038/s41467-020-17358-3
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发表时间：
2020-07-16
影响因子：
16.6
通讯作者：
Schiller, Herbert B.
中科院分区：
文献类型：
--
作者：
Strunz, Maximilian;Simon, Lukas M.;Schiller, Herbert B.
肺再生过程中转录程序的细胞类型特异性序列仍然难以捉摸。使用博来霉素肺损伤模型的时间序列单细胞RNA-seq，我们解析了28种细胞类型的转录动力学。轨迹建模与谱系追踪一起揭示了气道和肺泡干细胞在肺泡再生期间会聚在独特的Krt 8+过渡干细胞状态。这些细胞具有鳞状形态，特征为p53和NFkB激活，并显示细胞衰老的转录特征。Krt 8+状态出现在几种独立的肺损伤模型中，并在人肺纤维化中持续存在，在修复过程中与间充质和巨噬细胞形成了一个独特的细胞间通讯网络。我们产生了一个模型的基因调控程序导致Krt 8+过渡细胞和他们的终端分化为肺泡1型细胞。我们认为，在肺纤维化中，终末分化过程中受到干扰的分子检查点可能导致再生中间干细胞状态的异常持续。损伤修复的特征在于产生对组织恢复重要的瞬时细胞状态。在这里，作者提出了一个从小鼠博莱霉素肺损伤中恢复的单细胞RNA-seq图谱，并揭示了一种Krt 8+过渡性干细胞状态，这种状态在AT 1细胞再生之前并在人类肺纤维化中持续存在。
The cell type specific sequences of transcriptional programs during lung regeneration have remained elusive. Using time-series single cell RNA-seq of the bleomycin lung injury model, we resolved transcriptional dynamics for 28 cell types. Trajectory modeling together with lineage tracing revealed that airway and alveolar stem cells converge on a unique Krt8+transitional stem cell state during alveolar regeneration. These cells have squamous morphology, feature p53 and NFkB activation and display transcriptional features of cellular senescence. The Krt8+ state appears in several independent models of lung injury and persists in human lung fibrosis, creating a distinct cell-cell communication network with mesenchyme and macrophages during repair. We generated a model of gene regulatory programs leading to Krt8+transitional cells and their terminal differentiation to alveolar type-1 cells. We propose that in lung fibrosis, perturbed molecular checkpoints on the way to terminal differentiation can cause aberrant persistence of regenerative intermediate stem cell states. Injury repair is characterized by the generation of transient cell states important for tissue recovery. Here, the authors present a single cell RNA-seq map of recovery from bleomycin lung injury in mice and uncover a Krt8+ transitional stem cell state that precedes the regeneration of AT1 cells and persists in human lung fibrosis.