Adult stem cell-derived complete lung organoid models emulate lung disease in COVID-19.
Adult stem cell-derived complete lung organoid models emulate lung disease in COVID-19.
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作者：
Tindle C;Fuller M;Fonseca A;Taheri S;Ibeawuchi SR;Beutler N;Katkar GD;Claire A;Castillo V;Hernandez M;Russo H;Duran J;Crotty Alexander LE;Tipps A;Lin G;Thistlethwaite PA;Chattopadhyay R;Rogers TF;Sahoo D;Ghosh P;Das S
导致新冠肺炎的SARS-CoV-2病毒会在肺部造成广泛的损害，导致过度热情的免疫反应，其来源尚不清楚。我们提出了一种可扩展的、可繁殖的、个性化的、经济高效的成人干细胞来源的人肺器官模型，该模型包括近端和远端呼吸道上皮。用SARS-CoV-2感染成人肺器官(ALO)、原代呼吸道细胞或HIPSC来源的肺泡II型(AT2)细胞，建立新冠肺炎体外肺模型。感染的ALO单分子层最好地概括了不同队列的新冠肺炎患者呼吸道样本中的转录转录特征。呼吸道(近端)细胞对于持续的病毒感染至关重要，而在致死性疾病中，远端肺泡分化(AT2，→，AT1)对于增强过度热情的宿主免疫反应至关重要；具有良好混合的近端呼吸道成分的ALO单层概括了这两种情况。这一发现验证了新冠肺炎的人类肺模型，该模型可以立即用于研究新冠肺炎的发病机制，并审查新的治疗方法和疫苗。这项工作得到了美国国立卫生研究院(NIH)1R01DK107585-01A1、3R01DK107585-05S1(对SD)、R01-AI141630、CA100768和CA160911(对PG)和R01-AI 155696(对PG、DS和SD)、R00-CA151673和R01-GM138385(对DS)、R01-HL32225(对PT)、UCOP-R00RG2642(对SD和PG)、UCOP-R01RG3780(对P.G.和D.S)和圣地亚哥卫生桑福德临床干细胞中心(P.G、S.D、D.S)的飞行员奖的支持。GDK得到了美国免疫学家协会计算科学家和免疫学家交叉点奖学金计划的支持。洛杉矶分校的工资部分是由退伍军人事务部圣地亚哥医疗系统支持的。这份手稿包括加州大学圣地亚哥分校基因组医学研究所(IGC)使用Illumina NovaSeq 6000产生的数据，该仪器是在国家卫生研究院SIG赠款的资助下购买的(#S10 OD026929)。
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. This work was supported by the National Institutes for Health (NIH) grants 1R01DK107585-01A1, 3R01DK107585-05S1 (to SD); R01-AI141630, CA100768 and CA160911 (to PG) and R01-AI 155696 (to PG, DS and SD); R00-CA151673 and R01-GM138385 (to DS), R01- HL32225 (to PT), UCOP-R00RG2642 (to SD and PG), UCOP-R01RG3780 (to P.G. and D.S) and a pilot award from the Sanford Stem Cell Clinical Center at UC San Diego Health (P.G, S.D, D.S). GDK was supported through The American Association of Immunologists Intersect Fellowship Program for Computational Scientists and Immunologists. L.C.A's salary was supported in part by the VA San Diego Healthcare System. This manuscript includes data generated at the UC San Diego Institute of Genomic Medicine (IGC) using an Illumina NovaSeq 6000 that was purchased with funding from a National Institutes of Health SIG grant (#S10 OD026929).