Therapeutic antibodies reveal Notch control of transdifferentiation in the adult lung

Lafkas Daniel; Shelton Amy; Chiu Cecilia; Boenig Gladys de Leon; Chen Yongmei; Stawicki Scott S.; Siltanen Christian; Reichelt Mike; Zhou Meijuan; Wu Xiumin; Eastham-Anderson Jeffrey; Moore Heather; Roose-Girma Meron; Chinn Yvonne; Hang Julie Q.; Warming Soren; Egen Jackson; Lee Wyne P.; Austin Cary; Wu Yan; Payandeh Jian; Lowe John B.; Siebel Christian W.

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Therapeutic antibodies reveal Notch control of transdifferentiation in the adult lung

机译：治疗性抗体揭示了Notch对成年肺转分化的控制

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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.

机译：普遍的教条认为，通过Notch配体和受体进行的细胞间通讯决定了祖细胞分裂过程中的二元细胞命运决定，而分化谱系保持固定（1）。哺乳动物呼吸道中的粘液纤毛清除（2,3）取决于分泌细胞（俱乐部和杯状组织）和纤毛细胞来产生和运输粘液。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，以确定这些谱系从共同增殖的祖细胞中分化出来的命运（4-8）。与在快速分裂的群体中做出细胞命运决定的情况相反（9,10），体内成年稳态的气道上皮细胞寿命长（11-13），而对于有效的Notch信号传导的作用知之甚少在这种情况下。为了在成年哺乳动物中急性破坏锯齿状信号，在此我们产生了选择性靶向每个锯齿状旁系同源物的抗体拮抗剂，并确定了解释选择性的晶体结构。我们显示，在稳态条件下，没有细胞死亡或分裂增加的情况，急性锯齿状阻断可诱导俱乐部细胞快速和近乎完全丧失，并在纤毛细胞中伴随增加。命运分析表明，俱乐部细胞可直接转化为纤毛细胞而不会增殖，符合直接转分化的保守定义（14）。锯齿状抑制作用还可以逆转临床前哮喘模型中的杯状细胞化生，提供了治疗基础（15）。我们发现锯齿状拮抗作用减轻了细胞间转换的阻碍，这一发现揭示了出乎意料的可塑性，并建立了Notch调控转分化的模型。

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来源
《Nature》 |2015年第7580期|127-131|共5页
作者
Lafkas Daniel; Shelton Amy; Chiu Cecilia; Boenig Gladys de Leon; Chen Yongmei; Stawicki Scott S.; Siltanen Christian; Reichelt Mike; Zhou Meijuan; Wu Xiumin; Eastham-Anderson Jeffrey; Moore Heather; Roose-Girma Meron; Chinn Yvonne; Hang Julie Q.; Warming Soren; Egen Jackson; Lee Wyne P.; Austin Cary; Wu Yan; Payandeh Jian; Lowe John B.; Siebel Christian W.;
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作者单位

Genentech Inc, Dept Discovery Oncol, San Francisco, CA 94080 USA;

Genentech Inc, Dept Discovery Oncol, San Francisco, CA 94080 USA;

Genentech Inc, Dept Antibody Engn, San Francisco, CA 94080 USA;

Genentech Inc, Dept Biol Struct, San Francisco, CA 94080 USA;

Genentech Inc, Dept Antibody Engn, San Francisco, CA 94080 USA;

Genentech Inc, Dept Antibody Engn, San Francisco, CA 94080 USA;

Genentech Inc, Dept Discovery Oncol, San Francisco, CA 94080 USA;

Genentech Inc, Dept Pathol, San Francisco, CA 94080 USA;

Genentech Inc, Dept Translat Immunol, San Francisco, CA 94080 USA;

Genentech Inc, Dept Translat Immunol, San Francisco, CA 94080 USA;

Genentech Inc, Dept Pathol, San Francisco, CA 94080 USA;

Genentech Inc, Dept Discovery Immunol, San Francisco, CA 94080 USA;

Genentech Inc, Dept Mol Biol, San Francisco, CA 94080 USA;

Genentech Inc, Dept Prot Chem, San Francisco, CA 94080 USA;

Genentech Inc, Dept Prot Chem, San Francisco, CA 94080 USA;

Genentech Inc, Dept Mol Biol, San Francisco, CA 94080 USA;

Genentech Inc, Dept Discovery Immunol, San Francisco, CA 94080 USA;

Genentech Inc, Dept Translat Immunol, San Francisco, CA 94080 USA;

Genentech Inc, Dept Pathol, San Francisco, CA 94080 USA;

Genentech Inc, Dept Antibody Engn, San Francisco, CA 94080 USA;

Genentech Inc, Dept Biol Struct, San Francisco, CA 94080 USA;

Genentech Inc, Dept Pathol, San Francisco, CA 94080 USA;

Genentech Inc, Dept Discovery Oncol, San Francisco, CA 94080 USA;

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收录信息美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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Therapeutic antibodies reveal Notch control of transdifferentiation in the adult lung

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