Therapeutic antibodies reveal Notch control of transdifferentiation in the adult lung
Therapeutic antibodies reveal Notch control of transdifferentiation in the adult lung
复制标题
DOI：
10.1038/nature15715
复制
发表时间：
2015-12-03
期刊：
影响因子：
64.8
通讯作者：
Siebel, Christian W.
中科院分区：
文献类型：
--
作者：
Lafkas, Daniel;Shelton, Amy;Siebel, Christian W.
主流观点认为，在祖细胞分裂过程中，细胞间通过Notch配体和受体的通讯决定了二元细胞的命运，分化谱系保持不变(1)。哺乳动物呼吸道的黏液纤毛清除（2,3）依赖于分泌细胞（棒状和杯状）和纤毛细胞产生和运输黏液。在发育或修复过程中，密切相关的锯齿状配体（JAG1和JAG2）诱导Notch信号传导决定这些谱系的命运，因为它们来自一个共同的增殖祖细胞（4-8）。与细胞命运决定在快速分裂的群体中做出的情况相反（9,10），体内平衡的成人气道上皮细胞寿命很长（11-13），在这种情况下，对活性Notch信号的作用知之甚少。为了在成年哺乳动物中严重破坏Jagged信号，我们在这里产生了抗体拮抗剂，选择性地靶向每个Jagged旁链，并确定了解释选择性的晶体结构。我们发现，在稳态条件下，急性Jagged阻断诱导俱乐部细胞快速和近乎完全的损失，同时纤毛细胞增加，而不增加细胞死亡或分裂。Fate分析表明球杆细胞直接转化为纤毛细胞而不增殖，符合直接转分化的保守定义（14）。锯齿状抑制也逆转了临床前哮喘模型中的杯状细胞化生，为治疗提供了基础（15）。我们发现锯齿状拮抗解除了细胞间转化的阻断，揭示了意想不到的可塑性，并建立了Notch调控转分化的模型。
Prevailing dogma holds that cell-cell communication through Notch ligands and receptors determines binary cell fate decisions during progenitor cell divisions, with differentiated lineages remaining fixed(1). Mucociliary clearance(2,3) in mammalian respiratory airways depends on secretory cells (club and goblet) and ciliated cells to produce and transport mucus. During development or repair, the closely related Jagged ligands (JAG1 and JAG2) induce Notch signalling to determine the fate of these lineages as they descend from a common proliferating progenitor(4-8). In contrast to such situations in which cell fate decisions are made in rapidly dividing populations(9,10), cells of the homeostatic adult airway epithelium are long-lived(11-13), and little is known about the role of active Notch signalling under such conditions. To disrupt Jagged signalling acutely in adult mammals, here we generate antibody antagonists that selectively target each Jagged paralogue, and determine a crystal structure that explains selectivity. We show that acute Jagged blockade induces a rapid and near-complete loss of club cells, with a concomitant gain in ciliated cells, under homeostatic conditions without increased cell death or division. Fate analyses demonstrate a direct conversion of club cells to ciliated cells without proliferation, meeting a conservative definition of direct transdifferentiation(14). Jagged inhibition also reversed goblet cell metaplasia in a preclinical asthma model, providing a therapeutic foundation(15). Our discovery that Jagged antagonism relieves a blockade of cell-to-cell conversion unveils unexpected plasticity, and establishes a model for Notch regulation of transdifferentiation.