Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell Rep. 2021 May 11;35(6):109092. doi: 10.1016/j.celrep.2021.109092.
Alveolar epithelial type 2 (AT2) cells integrate signals from multiple molecular pathways to proliferate and differentiate to drive regeneration of the lung alveolus. Utilizing in vivo genetic and ex vivo organoid models, we investigated the role of Fgfr2 signaling in AT2 cells across the lifespan and during adult regeneration after influenza infection. We show that, although dispensable for adult homeostasis, Fgfr2 restricts AT2 cell fate during postnatal lung development. Using an unbiased computational imaging approach, we demonstrate that Fgfr2 promotes AT2 cell proliferation and restrains differentiation in actively regenerating areas after injury. Organoid assays reveal that Fgfr2-deficient AT2 cells remain competent to respond to multiple parallel proliferative inputs. Moreover, genetic blockade of AT2 cell cytokinesis demonstrates that cell division and differentiation are uncoupled during alveolar regeneration. These data reveal that Fgfr2 maintains AT2 cell fate, balancing proliferation and differentiation during lung alveolar regeneration.
肺泡上皮细胞 2 型 (AT2) 通过整合多种分子通路的信号来增殖和分化，从而驱动肺泡的再生。利用体内遗传和体外类器官模型，我们研究了 Fgfr2 信号在整个生命周期以及流感感染后成年期再生过程中在 AT2 细胞中的作用。我们发现，尽管在成年期稳态中不需要 Fgfr2，但它在出生后肺发育过程中限制了 AT2 细胞的命运。我们使用一种无偏的计算成像方法证明，Fgfr2 促进损伤后活跃再生区域的 AT2 细胞增殖并抑制分化。类器官测定显示，Fgfr2 缺陷的 AT2 细胞仍然能够对多种平行增殖信号做出反应。此外，对 AT2 细胞胞质分裂的基因阻断表明，在肺泡再生过程中，细胞分裂和分化是解耦的。这些数据表明，Fgfr2 维持 AT2 细胞的命运，在肺肺泡再生过程中平衡增殖和分化。
