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.

中文翻译：

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人类气道上皮信号反应图

受体介导的信号传导在组织再生中发挥核心作用，并且在疾病中失调。在这里，我们为模型再生人体组织（气道上皮）构建了信号响应图。我们分析了 17 种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。该图概括了已知气道上皮信号对这些途径的反应。它定义了基底细胞和分泌细胞化生中多种配体和多种配体特异性反应诱导的收敛状态。我们发现，多种途径诱导的典型分化丧失与细胞周期停滞相关，但这种停滞不足以阻止分化。使用信号传导-反应图谱，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，并确定了 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反应的框架。补充信息中包含了本文透明同行评审过程的记录。