Mori Munemasa, Mahoney John E, Stupnikov Maria R, Paez-Cortez Jesus R, Szymaniak Aleksander D, Varelas Xaralabos, Herrick Dan B, Schwob James, Zhang Hong, Cardoso Wellington V
Columbia Center for Human Development, Department of Medicine, Pulmonary Allergy Critical Care, Columbia University Medical Center, New York, NY 10032, USA.
Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Development. 2015 Jan 15;142(2):258-67. doi: 10.1242/dev.116855.
Basal cells are multipotent airway progenitors that generate distinct epithelial cell phenotypes crucial for homeostasis and repair of the conducting airways. Little is known about how these progenitor cells expand and transition to differentiation to form the pseudostratified airway epithelium in the developing and adult lung. Here, we show by genetic and pharmacological approaches that endogenous activation of Notch3 signaling selectively controls the pool of undifferentiated progenitors of upper airways available for differentiation. This mechanism depends on the availability of Jag1 and Jag2, and is key to generating a population of parabasal cells that later activates Notch1 and Notch2 for secretory-multiciliated cell fate selection. Disruption of this mechanism resulted in aberrant expansion of basal cells and altered pseudostratification. Analysis of human lungs showing similar abnormalities and decreased NOTCH3 expression in subjects with chronic obstructive pulmonary disease suggests an involvement of NOTCH3-dependent events in the pathogenesis of this condition.
基底细胞是多能气道祖细胞，可产生对传导气道的稳态和修复至关重要的不同上皮细胞表型。关于这些祖细胞如何在发育中的和成年肺中扩增并过渡到分化以形成假复层气道上皮，我们知之甚少。在此，我们通过遗传学和药理学方法表明，Notch3信号的内源性激活选择性地控制了可用于分化的上呼吸道未分化祖细胞池。该机制取决于Jag1和Jag2的可用性，并且是产生一群副基底细胞的关键，这些副基底细胞随后激活Notch1和Notch2以进行分泌性多纤毛细胞命运选择。该机制的破坏导致基底细胞异常扩增和假复层改变。对患有慢性阻塞性肺疾病的受试者的人肺分析显示出类似的异常且NOTCH3表达降低，这表明NOTCH3依赖性事件参与了该疾病的发病机制。
