Warren Rachel, Klinkhammer Kylie, Lyu Handeng, Knopp Joseph, Yuan Tingting, Yao Changfu, Stripp Barry, De Langhe Stijn P
Department of Medicine, Division of Pulmonary and Critical Medicine, Mayo Clinic, Rochester, MN, USA.
Department of Medicine, Division of Pulmonary, Allergy & Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Nat Commun. 2024 Dec 5;15(1):10624. doi: 10.1038/s41467-024-54997-2.
Idiopathic pulmonary fibrosis (IPF) is a progressive respiratory scarring disease arising from the maladaptive differentiation of lung stem cells into bronchial epithelial cells rather than into alveolar type 1 (AT1) cells, which are responsible for gas exchange. Here, we report that healthy lungs maintain their stem cells through tonic Hippo and β-catenin signaling, which promote Yap/Taz degradation and allow for low-level expression of the Wnt target gene Myc. Inactivation of upstream activators of the Hippo pathway in lung stem cells inhibits this tonic β-catenin signaling and Myc expression and promotes their Taz-mediated differentiation into AT1 cells. Vice versa, increased Myc in collaboration with Yap promotes the differentiation of lung stem cells along the basal and myoepithelial-like lineages allowing them to invade and bronchiolize the lung parenchyma in a process reminiscent of submucosal gland development. Our findings indicate that stem cells exhibiting the highest Myc levels become supercompetitors that drive remodeling, whereas loser cells with lower Myc levels terminally differentiate into AT1 cells.
特发性肺纤维化（IPF）是一种进行性的呼吸性瘢痕疾病，它源于肺干细胞向支气管上皮细胞而非负责气体交换的1型肺泡（AT1）细胞的适应性分化异常。在此，我们报告健康的肺通过持续性的Hippo和β-连环蛋白信号通路维持其干细胞，这两种信号通路促进Yap/Taz降解，并允许Wnt靶基因Myc的低水平表达。肺干细胞中Hippo通路上游激活因子的失活会抑制这种持续性的β-连环蛋白信号传导和Myc表达，并促进它们通过Taz介导分化为AT1细胞。反之，Myc与Yap协同增加，会促进肺干细胞沿基底和肌上皮样谱系分化，使它们能够在类似于黏膜下腺发育的过程中侵入肺实质并使其细支气管化。我们的研究结果表明，表现出最高Myc水平的干细胞成为驱动重塑的超级竞争者，而Myc水平较低的“失败者”细胞则终末分化为AT1细胞。
