Department of Pulmonary Medicine, the University of Texas MD Anderson Cancer Center, Houston, Texas and.
Graduate Program in Developmental Biology, Baylor College of Medicine, Houston, Texas.
Am J Respir Cell Mol Biol. 2022 Sep;67(3):389-401. doi: 10.1165/rcmb.2021-0421OC.
The lung epithelium forms the first barrier against respiratory pathogens and noxious chemicals; however, little is known about how more than 90% of this barrier, made of AT1 (alveolar type 1) cells, responds to injury. Using the Sendai virus to model natural infection in mice, we find evidence that AT1 cells have an intermediary role by persisting in areas depleted of AT2 cells, upregulating IFN responsive genes, and receding from invading airway cells. Sendai virus infection mobilizes airway cells to form alveolar SOX2 (Sry-box 2) clusters without differentiating into AT1 or AT2 cells. Large AT2 cell-depleted areas remain covered by AT1 cells, which we name "AT2-less regions", and are replaced by SOX2 clusters spreading both basally and luminally. AT2 cell proliferation and differentiation are largely confined to topologically distal regions and form alveolar surface, with limited contribution to repairs of AT2-less regions. Time-course single-cell RNA sequencing profiling and RNAscope validation suggest enhanced immune responses and altered growth signals in AT1 cells. Our comprehensive spatiotemporal and genomewide study highlights the hitherto unappreciated role of AT1 cells in lung injury-repair.
肺上皮细胞构成了抵御呼吸道病原体和有害化学物质的第一道屏障；然而，人们对超过 90%的由 AT1（肺泡 1 型）细胞组成的屏障如何对损伤做出反应知之甚少。我们使用仙台病毒在小鼠中模拟自然感染，发现 AT1 细胞通过在 AT2 细胞耗竭的区域持续存在、上调 IFN 反应基因以及从入侵的气道细胞中退缩，起到了中间作用的证据。仙台病毒感染动员气道细胞形成没有分化为 AT1 或 AT2 细胞的肺泡 SOX2（Sry-box 2）簇。大的 AT2 细胞耗竭区域仍然被 AT1 细胞覆盖，我们将其命名为“无 AT2 区域”，并被 SOX2 簇在基底和管腔方向扩展所取代。AT2 细胞的增殖和分化主要局限于拓扑上的远端区域，并形成肺泡表面，对无 AT2 区域的修复贡献有限。单细胞 RNA 测序分析和 RNAscope 验证的时间过程提示 AT1 细胞中增强的免疫反应和改变的生长信号。我们的全面时空和全基因组研究强调了 AT1 细胞在肺损伤修复中的先前未被认识到的作用。
