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Progenitor identification and SARS-CoV-2 infection in human distal lung organoids

机译：祖母鉴定和SARS-COV-2在人远端肺器官中的感染

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摘要

The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange. Three-dimensional in vitro human distal lung culture systems would strongly facilitate the investigation of pathologies such as interstitial lung disease, cancer and coronavirus disease 2019 (COVID-19) pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we describe the development of a long-term feeder-free, chemically defined culture system for distal lung progenitors as organoids derived from single adult human alveolar epithelial type II (AT2) or KRT5~(+)basal cells. AT2 organoids were able to differentiate into AT1 cells, and basal cell organoids developed lumens lined with differentiated club and ciliated cells. Single-cell analysis of KRT5~(+)cells in basal organoids revealed a distinct population of ITGA6~(+)ITGB4~(+)mitotic cells, whose offspring further segregated into a TNFRSF12A~(hi)subfraction that comprised about ten per cent of KRT5~(+)basal cells. This subpopulation formed clusters within terminal bronchioles and exhibited enriched clonogenic organoid growth activity. We created distal lung organoids with apical-out polarity to present ACE2 on the exposed external surface, facilitating infection of AT2 and basal cultures with SARS-CoV-2 and identifying club cells as a target population. This long-term, feeder-free culture of human distal lung organoids, coupled with single-cell analysis, identifies functional heterogeneity among basal cells and establishes a facile in vitro organoid model of human distal lung infections, including COVID-19-associated pneumonia.
机译：远端肺含有终端支气管和肺泡，便于气体交换。三维体外人体远端肺部培养系统将强烈促进对肺病，癌症和冠状病毒疾病（Covid-19）肺炎（Covid-19）肺炎引起的病理学的调查（Covid-19）引起的严重急性呼吸综合征冠状病毒2（SARS-COV-2）。在这里，我们描述了用于远端肺祖细胞体的长期饲养，化学定义的培养系统的发展，作为衍生自单身人肺泡上皮II（AT2）或KRT5〜（+）基底细胞的有机体。 AT2有机体能够分化为AT1细胞，基底细胞器产生衬里的流明，含有分化的球杆和纤毛细胞。基底有机体中Krt5〜（+）细胞的单细胞分析显示出ITGA6〜（+）ITGB4〜（+）有丝分裂细胞的不同群体，其后代进一步分离成TNFRSF12A〜（HI）子次级，其包括约10％ Krt5〜（+）基底细胞。该亚群在末端支气管内形成簇，并表现出富集的克隆核酸有机体生长活性。我们用顶端输出极性创造了远端肺器子骨，以在暴露的外表面上呈现ACE2，促进用SARS-COV-2感染AT2和基础培养物，并将杆菌细胞鉴定为靶群。这种长期饲养的人远端肺器有机体培养物，与单细胞分析相结合，鉴定了基底细胞之间的功能异质性，并建立了人类远端肺部感染的体外细胞体模型，包括Covid-19相关的肺炎。

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  • 来源
    《Nature》 |2020年第7839期|670-675|共6页
  • 作者

    Ameen A Salahudeen; Shannon S Choi; Arjun Rustagi; Junjie Zhu; Vincent van Unen; Sean M de la O; Ryan A Flynn; Mar Margalef-Català; António J M Santos; Jihang Ju; Arpit Batish; Tatsuya Usui; Grace X Y Zheng; Caitlin E Edwards; Lisa E Wagar; Vincent Luca; Benedict Anchang; Monica Nagendran; Khanh Nguyen; Daniel J Hart; Jessica M Terry; Phillip Belgrader; Solongo B Ziraldo; Tarjei S Mikkelsen; Pehr B Harbury; Jeffrey S Glenn; K Christopher Garcia; Mark M Davis; Ralph S Baric; Chiara Sabatti; Manuel R Amieva; Catherine A Blish; Tushar J Desai; Calvin J Kuo;

  • 作者单位

    Division of Hematology Department of Medicine Stanford University School of Medicine|Division of Hematology and Oncology Department of Medicine University of Illinois at Chicago College of Medicine;

    Division of Hematology Department of Medicine Stanford University School of Medicine;

    Division of Infectious Disease and Geographic Medicine Department of Medicine Stanford University School of Medicine;

    Stanford University School of Engineering Department of Electrical Engineering;

    Department of Microbiology and Immunology Stanford University School of Medicine|Stanford Institute of Immunity Transplantation and Infection Stanford University School of Medicine;

    Division of Hematology Department of Medicine Stanford University School of Medicine;

    Stanford ChEM-H Stanford University|Department of Chemistry Stanford University;

    Department of Pediatrics Stanford University School of Medicine;

    Division of Hematology Department of Medicine Stanford University School of Medicine;

    Division of Hematology Department of Medicine Stanford University School of Medicine;

    Division of Hematology Department of Medicine Stanford University School of Medicine;

    Division of Hematology Department of Medicine Stanford University School of Medicine;

    Genomics;

    Department of Epidemiology University of North Carolina at Chapel Hill;

    Department of Microbiology and Immunology Stanford University School of Medicine|Stanford Institute of Immunity Transplantation and Infection Stanford University School of Medicine;

    Department of Molecular and Cellular Physiology Stanford University School of Medicine;

    Division of Biomedical Data Science Department of Medicine Stanford University School of Medicine;

    Division of Pulmonary Allergy and Critical Care Department of Medicine Stanford University School of Medicine;

    Division of Gastroenterology Department of Medicine Stanford University School of Medicine;

    Division of Hematology Department of Medicine Stanford University School of Medicine;

    Genomics;

    Genomics;

    Genomics;

    Genomics;

    Department of Biochemistry Stanford University School of Medicine;

    Department of Microbiology and Immunology Stanford University School of Medicine|Division of Gastroenterology Department of Medicine Stanford University School of Medicine;

    Department of Molecular and Cellular Physiology Stanford University School of Medicine|Howard Hughes Medical Institute Stanford University School of Medicine;

    Department of Microbiology and Immunology Stanford University School of Medicine|Stanford Institute of Immunity Transplantation and Infection Stanford University School of Medicine|Howard Hughes Medical Institute Stanford University School of Medicine;

    Department of Epidemiology University of North Carolina at Chapel Hill|Department of Microbiology and Immunology University of North Carolina at Chapel Hill;

    Division of Biomedical Data Science Department of Medicine Stanford University School of Medicine;

    Department of Microbiology and Immunology Stanford University School of Medicine|Department of Pediatrics Stanford University School of Medicine;

    Division of Infectious Disease and Geographic Medicine Department of Medicine Stanford University School of Medicine|Chan Zuckerberg Biohub;

    Division of Pulmonary Allergy and Critical Care Department of Medicine Stanford University School of Medicine;

    Division of Hematology Department of Medicine Stanford University School of Medicine;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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