Human Lung Stem Cell-Based Alveolospheres Provide Insights into SARS-CoV-2-Mediated Interferon Responses and Pneumocyte Dysfunction.
Human Lung Stem Cell-Based Alveolospheres Provide Insights into SARS-CoV-2-Mediated Interferon Responses and Pneumocyte Dysfunction.
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DOI：
10.1016/j.stem.2020.10.005
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发表时间：
2020-12-03
期刊：
影响因子：
23.9
通讯作者：
Tata PR
中科院分区：
文献类型：
--
作者：
Katsura H;Sontake V;Tata A;Kobayashi Y;Edwards CE;Heaton BE;Konkimalla A;Asakura T;Mikami Y;Fritch EJ;Lee PJ;Heaton NS;Boucher RC;Randell SH;Baric RS;Tata PR
冠状病毒感染引起弥漫性肺泡损伤，导致急性呼吸窘迫综合征。缺乏人肺泡上皮细胞的离体模型阻碍了对2019冠状病毒病（COVID-19）发病机制的理解。在这里，我们报告了一个无饲养层，可扩展的，化学定义，和模块化的肺泡培养系统的人肺泡2型细胞/肺细胞的繁殖和分化的原代肺组织。培养的肺细胞表达严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）受体血管紧张素转换酶受体2型（ACE 2），并可被病毒感染。感染肺泡球的转录组和组织学分析反映了COVID-19肺的特征，包括干扰素（IFN）介导的炎症反应的出现，表面活性蛋白的丢失和细胞凋亡。用干扰素治疗肺泡球概括了病毒感染的特征，包括细胞死亡。相比之下，用低剂量IFN预处理的肺泡球显示病毒复制减少，表明IFN对SARS-CoV-2的预防有效性。因此，基于人类干细胞的肺泡球为COVID-19发病机制提供了新的见解，并可作为理解人类呼吸系统疾病的模型。成人肺干细胞AT 2对SARS-CoV-2感染的无基质长期扩增和分化反应反映了COVID-19肺的特征感染的AT 2上调IFN和凋亡途径并减少表面活性剂低剂量IFN预处理阻断SARS-CoV-2在肺泡球中的复制Tata及其同事报告了成人原代肺泡干细胞长期扩增和分化的定义条件。培养的AT 2有助于SARS-CoV-2感染，并引发反映COVID-19组织病理学的全转录组变化，包括炎症反应上调、细胞死亡和表面活性剂表达下调，导致肺细胞功能障碍。
Coronavirus infection causes diffuse alveolar damage leading to acute respiratory distress syndrome. The absence of ex vivo models of human alveolar epithelium is hindering an understanding of coronavirus disease 2019 (COVID-19) pathogenesis. Here, we report a feeder-free, scalable, chemically defined, and modular alveolosphere culture system for the propagation and differentiation of human alveolar type 2 cells/pneumocytes derived from primary lung tissue. Cultured pneumocytes express the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor angiotensin-converting enzyme receptor type-2 (ACE2) and can be infected with virus. Transcriptome and histological analysis of infected alveolospheres mirror features of COVID-19 lungs, including emergence of interferon (IFN)-mediated inflammatory responses, loss of surfactant proteins, and apoptosis. Treatment of alveolospheres with IFNs recapitulates features of virus infection, including cell death. In contrast, alveolospheres pretreated with low-dose IFNs show a reduction in viral replication, suggesting the prophylactic effectiveness of IFNs against SARS-CoV-2. Human stem cell-based alveolospheres, thus, provide novel insights into COVID-19 pathogenesis and can serve as a model for understanding human respiratory diseases. Stroma-free long-term expansion and differentiation of adult human lung stem cells AT2 response to SARS-CoV-2 infection mirrors features of COVID-19 lungs Infected AT2s upregulate IFNs and apoptotic pathways and decrease surfactants Low-dose IFN pre-treatment blocks SARS-CoV-2 replication in alveolospheres Tata and colleagues report defined conditions for long-term expansion and differentiation of adult human primary alveolar stem cells. Cultured AT2s are conducive to SARS-CoV-2 infection and elicit transcriptome-wide changes that mirror COVID-19 histopathology, including upregulation of inflammatory responses, cell death, and downregulation of surfactant expression, leading to pneumocyte dysfunction.
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影响因子：
64.5
作者：
Hou, Yixuan J.;Okuda, Kenichi;Baric, Ralph S.
通讯作者：
Baric, Ralph S.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
23.9
作者：
Jacob A;Morley M;Hawkins F;McCauley KB;Jean JC;Heins H;Na CL;Weaver TE;Vedaie M;Hurley K;Hinds A;Russo SJ;Kook S;Zacharias W;Ochs M;Traber K;Quinton LJ;Crane A;Davis BR;White FV;Wambach J;Whitsett JA;Cole FS;Morrisey EE;Guttentag SH;Beers MF;Kotton DN
通讯作者：
Kotton DN
DOI：
10.1242/dev.163014
发表时间：
2018-05-11
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Chung MI;Bujnis M;Barkauskas CE;Kobayashi Y;Hogan BLM
通讯作者：
Hogan BLM
DOI：
10.1074/jbc.ac120.013788
发表时间：
2020-10-09
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Felgenhauer U;Schoen A;Gad HH;Hartmann R;Schaubmar AR;Failing K;Drosten C;Weber F
通讯作者：
Weber F