Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Nat Commun. 2023 Dec 19;14(1):8452. doi: 10.1038/s41467-023-44184-0.
Lung epithelial regeneration after acute injury requires coordination cellular coordination to pattern the morphologically complex alveolar gas exchange surface. During adult lung regeneration, Wnt-responsive alveolar epithelial progenitor (AEP) cells, a subset of alveolar type 2 (AT2) cells, proliferate and transition to alveolar type 1 (AT1) cells. Here, we report a refined primary murine alveolar organoid, which recapitulates critical aspects of in vivo regeneration. Paired scRNAseq and scATACseq followed by transcriptional regulatory network (TRN) analysis identified two AT1 transition states driven by distinct regulatory networks controlled in part by differential activity of Nkx2-1. Genetic ablation of Nkx2-1 in AEP-derived organoids was sufficient to cause transition to a proliferative stressed Krt8 state, and AEP-specific deletion of Nkx2-1 in adult mice led to rapid loss of progenitor state and uncontrolled growth of Krt8 cells. Together, these data implicate dynamic epigenetic maintenance via Nkx2-1 as central to the control of facultative progenitor activity in AEPs.
急性损伤后肺上皮的再生需要细胞协调来塑造形态复杂的肺泡气体交换表面。在成人肺再生过程中，Wnt 反应性肺泡上皮祖细胞（AEP）细胞，即肺泡 II 型（AT2）细胞的一个亚群，增殖并向肺泡 I 型（AT1）细胞转化。在这里，我们报告了一种经过改良的原代小鼠肺泡类器官，它再现了体内再生的关键方面。配对的单细胞 RNA 测序和 scATAC 测序，以及转录调控网络（TRN）分析，确定了由两个不同的调控网络驱动的 AT1 转化状态，这些网络部分受到 Nkx2-1 活性的差异控制。在 AEP 衍生的类器官中遗传消融 Nkx2-1 足以导致向增殖应激的 Krt8 状态转化，而在成年小鼠中特异性敲除 AEP 中的 Nkx2-1 会导致祖细胞状态的快速丧失和 Krt8 细胞的失控生长。总之，这些数据表明，通过 Nkx2-1 的动态表观遗传维持对于 AEPs 中选择性祖细胞活性的控制至关重要。
