小柯机器人

科学家开发出人类远端肺脏的类器官模型
2020-11-27 13:46

美国斯坦福大学Calvin J. Kuo等研究人员合作开发出人类远端肺脏的类器官模型。该研究于2020年11月25日在线发表于国际一流学术期刊《自然》。

研究人员开发了远端祖细胞的长期无饲养层、化学定义培养物,其作为源自单个成年人类肺泡上皮II型(AT2)或KRT5+基底细胞的类器官。AT2类器官表现出AT1转分化潜能,而基底细胞类器官发展出由分化的棒状和纤毛细胞排列的内腔。对基底类器官KRT5+细胞的单细胞分析显示出一个独特的ITGA6+ ITGB4+有丝分裂群体,其增殖进一步分离为TNFRSF12Ahi亚群,占KRT5+基底细胞的10%,位于末端细支气管内的簇中,并表现出丰富的克隆形成类器官生长活性。
 
研究人员创建了远端肺脏类器官,其顶端朝外,从而在暴露的外表面上表达ACE2,可促进SARS-CoV-2感染。人类远端肺脏的长期无饲养层类器官培养物以及单细胞分析,可鉴定基底细胞功能异质性,并为人类远端肺部感染(包括与COVID-19相关的肺炎)建立了简便的体外类器官模型。
 
据介绍,远端肺脏包含促进气体交换的末端细支气管和肺泡。三维体外人远端肺培养系统将极大地促进病理研究,包括间质性肺疾病、癌症和SARS-CoV-2相关的COVID-19肺炎。
 
附:英文原文

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

Author: Ameen A. Salahudeen, Shannon S. Choi, Arjun Rustagi, Junjie Zhu, Vincent van Unen, Sean M. de la O, Ryan A. Flynn, Mar Margalef-Catal, Antnio 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

Issue&Volume: 2020-11-25

Abstract: The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange. Three-dimensional in vitro human distal lung culture systems would strongly facilitate investigation of pathologies including interstitial lung disease, cancer, and SARS-CoV-2-associated COVID-19 pneumonia. We generated long-term feeder-free, chemically defined culture of distal lung progenitors as organoids derived from single adult human alveolar epithelial type II (AT2) or KRT5+ basal cells. AT2 organoids exhibited AT1 transdifferentiation potential while basal cell organoids developed lumens lined by differentiated club and ciliated cells. Single cell analysis of basal organoid KRT5+ cells revealed a distinct ITGA6+ITGB4+ mitotic population whose proliferation further segregated to a TNFRSF12Ahi subfraction comprising ~10% of KRT5+ basal cells, residing in clusters within terminal bronchioles and exhibiting enriched clonogenic organoid growth activity. Distal lung organoids were created with apical-out polarity to display ACE2 on the exposed external surface, facilitating SARS-CoV-2 infection of AT2 and basal cultures and identifying club cells as a novel target population. This long-term, feeder-free organoid culture of human distal lung, coupled with single cell analysis, identifies unsuspected basal cell functional heterogeneity and establishes a facile in vitro organoid model for human distal lung infections including COVID-19-associated pneumonia.

DOI: 10.1038/s41586-020-3014-1

Source: https://www.nature.com/articles/s41586-020-3014-1

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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