SARS-CoV-2, the virus responsible for COVID-19, causes widespread damage in the lungs in the setting of an overzealous immune response whose origin remains unclear. We present a scalable, propagable, personalized, cost-effective adult stem cell-derived human lung organoid model that is complete with both proximal and distal airway epithelia. Monolayers derived from adult lung organoids (ALOs), primary airway cells, or hiPSC-derived alveolar type-II (AT2) pneumocytes were infected with SARS-CoV-2 to create in vitro lung models of COVID-19. Infected ALO-monolayers best recapitulated the transcriptomic signatures in diverse cohorts of COVID-19 patient-derived respiratory samples. The airway (proximal) cells were critical for sustained viral infection whereas distal alveolar differentiation (AT2→AT1) was critical for mounting the overzealous host immune response in fatal disease; ALO monolayers with well-mixed proximodistal airway components recapitulated both. Findings validate a human lung model of COVID-19 which can be immediately utilized to investigate COVID-19 pathogenesis, and vet new therapies and vaccines.

中文翻译：

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成人干细胞衍生的完整肺类器官模型在 COVID-19 中模拟肺病

SARS-CoV-2 是导致 COVID-19 的病毒，在过度狂热的免疫反应的情况下，它会在肺部造成广泛的损害，其起源仍不清楚。我们提出了一种可扩展的、可传播的、个性化的、具有成本效益的成人干细胞衍生的人肺类器官模型，该模型具有近端和远端气道上皮细胞。来自成人肺类器官 (ALO)、初级气道细胞或 hiPSC 衍生的肺泡 II 型 (AT2) 肺细胞的单层被 SARS-CoV-2 感染，以创建 COVID-19 的体外肺模型。受感染的 ALO 单层最好地概括了 COVID-19 患者衍生的呼吸道样本的不同队列中的转录组特征。气道（近端）细胞对于持续的病毒感染至关重要，而远端肺泡分化（AT2→AT1）对于在致命疾病中引发过度热情的宿主免疫反应至关重要；具有良好混合的近端气道成分的 ALO 单层概括了两者。研究结果验证了 COVID-19 的人肺模型，该模型可立即用于研究 COVID-19 发病机制，并审查新疗法和疫苗。