Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore 560065, India; Manipal Academy of Higher Education (MAHE), Madhav Nagar, Manipal 576104, India.
Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore 560065, India; The University of Trans-Disciplinary Health Sciences and Technology (TDU), Yelahanka 560064, Bangalore, India.
Cell Rep. 2024 Sep 24;43(9):114654. doi: 10.1016/j.celrep.2024.114654. Epub 2024 Aug 24.
Lower airway club cells (CCs) serve the dual roles of a secretory cell and a stem cell. Here, we probe how the CC fate is regulated. We find that, in response to acute perturbation of Notch signaling, CCs adopt distinct fates. Although the vast majority transdifferentiate into multiciliated cells, a "variant" subpopulation (v-CCs), juxtaposed to neuroepithelial bodies (NEBs; 5%-10%) and located at bronchioalveolar duct junctions (>80%), does not. Instead, v-CCs transition into lineage-ambiguous states but can revert to a CC fate upon restoration of Notch signaling and repopulate the airways with CCs and multiciliated cells. The v-CC response to Notch inhibition is dependent on localized activation of β-catenin in v-CCs. We propose that the CC fate is stabilized by canonical Notch signaling, that airways are susceptible to perturbations to this pathway, and that NEBs/terminal bronchioles comprise niches that modulate CC plasticity via β-catenin activation to facilitate airway repair post Notch inhibition.
下呼吸道 club 细胞 (CCs) 具有分泌细胞和干细胞的双重作用。在这里，我们探讨了 CC 命运是如何受到调控的。我们发现，在 Notch 信号通路受到急性干扰时，CC 会采取不同的命运。尽管绝大多数分化为多纤毛细胞，但一个“变异”亚群 (v-CCs) 毗邻神经上皮体 (NEBs；5%-10%)，并位于支气管肺泡导管交界处 (>80%)，则不会。相反，v-CCs 过渡到谱系不确定状态，但在 Notch 信号恢复和重新填充 CC 和多纤毛细胞后，可恢复为 CC 命运。v-CC 对 Notch 抑制的反应依赖于 v-CC 中局部激活的β-catenin。我们提出，CC 命运受经典 Notch 信号的稳定，气道易受到该途径的干扰，并且 NEBs/终末细支气管通过激活β-catenin 构成调节 CC 可塑性的小生境，以促进 Notch 抑制后的气道修复。
