PDF(Pubmed)
Abstract：
Receptor-mediated signaling plays a central role in tissue regeneration, and it is dysregulated in disease. Here, we build a signaling-response map for a model regenerative human tissue: the airway epithelium. We analyzed the effect of 17 receptor-mediated signaling pathways on organotypic cultures to determine changes in abundance and phenotype of epithelial cell types. This map recapitulates the gamut of known airway epithelial signaling responses to these pathways. It defines convergent states induced by multiple ligands and diverse, ligand-specific responses in basal cell and secretory cell metaplasia. We show that loss of canonical differentiation induced by multiple pathways is associated with cell-cycle arrest, but that arrest is not sufficient to block differentiation. Using the signaling-response map, we show that a TGFB1-mediated response underlies specific aberrant cells found in multiple lung diseases and identify interferon responses in COVID-19 patient samples. Thus, we offer a framework enabling systematic evaluation of tissue signaling responses. A record of this paper\'s transparent peer review process is included in the supplemental information.
摘要：
受体介导的信号在组织再生中起着核心作用，它在疾病中失调。这里,我们建立了一个再生人体组织模型的信号反应图:气道上皮.我们分析了17个受体介导的信号通路对器官型培养物的影响，以确定上皮细胞类型的丰度和表型的变化。该图谱概括了对这些途径的已知气道上皮信号传导反应的色域。它定义了由多个配体和多样化诱导的会聚态，在基底细胞和分泌细胞化生中的配体特异性反应。我们表明，由多个途径诱导的典型分化的丧失与细胞周期停滞有关，但是逮捕不足以阻止分化。使用信令-响应图，我们表明，TGFB1介导的反应是多种肺部疾病中发现的特定异常细胞的基础，并鉴定了COVID-19患者样本中的干扰素反应。因此，我们提供了一个能够系统评估组织信号应答的框架.补充信息中包含了本文透明的同行评审过程的记录。
