Notch2 Is Required for Inflammatory Cytokine-Driven Goblet Cell Metaplasia in the Lung
Notch2 Is Required for Inflammatory Cytokine-Driven Goblet Cell Metaplasia in the Lung
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DOI：
10.1016/j.celrep.2014.12.017
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发表时间：
2015-01-13
期刊：
影响因子：
8.8
通讯作者：
Jaffe, Aron B.
中科院分区：
文献类型：
--
作者：
Danahay, Henry;Pessotti, Angelica D.;Jaffe, Aron B.
上皮细胞类型的平衡和分布是维持组织稳态所必需的。气道疾病的一个标志是上皮重塑，导致杯状细胞数量增加和粘液过度产生。在传导气道中，基底细胞作为分泌细胞和纤毛细胞的祖细胞。为了确定调节基底细胞命运的机制，我们开发了一种可筛选的气道上皮形态发生的3D培养系统。我们使用一系列分泌蛋白进行了高通量筛选，并鉴定了特异性偏向杯状细胞命运的基底细胞分化的炎性细胞因子，最终导致粘液产生增加。我们还证明了Notch2在体外和体内马槟榔诱导的杯状细胞化生中的特异性需求。我们的结论是，抑制刻缺蛋白2防止杯状细胞化生诱导的广泛的刺激，并提出刻缺蛋白2中和作为一种治疗策略，用于预防杯状细胞化生在气道疾病。
The balance and distribution of epithelial cell types is required to maintain tissue homeostasis. A hallmark of airway diseases is epithelial remodeling, leading to increased goblet cell numbers and an overproduction of mucus. In the conducting airway, basal cells act as progenitors for both secretory and ciliated cells. To identify mechanisms regulating basal cell fate, we developed a screenable 3D culture system of airway epithelial morphogenesis. We performed a high-throughput screen using a collection of secreted proteins and identified inflammatory cytokines that specifically biased basal cell differentiation toward a goblet cell fate, culminating in enhanced mucus production. We also demonstrate a specific requirement for Notch2 in cytokine-induced goblet cell metaplasia in vitro and in vivo. We conclude that inhibition of Notch2 prevents goblet cell metaplasia induced by a broad range of stimuli and propose Notch2 neutralization as a therapeutic strategy for preventing goblet cell metaplasia in airway diseases.