A human three-dimensional neural-perivascular 'assembloid' promotes astrocytic development and enables modeling of SARS-CoV-2 neuropathology

被引：107

作者：

Wang, Lu ^{[1
,2
]}

Sievert, David ^{[1
,2
]}

Clark, Alex E. ^{[3
]}

Lee, Sangmoon ^{[1
,2
]}

Federman, Hannah ^{[1
,2
,4
]}

Gastfriend, Benjamin D. ^{[5
]}

Shusta, Eric V. ^{[5
,6
]}

Palecek, Sean P. ^{[5
]}

Carlin, Aaron F. ^{[3
]}

Gleeson, Joseph G. ^{[1
,2
,7
]}

机构：

[1] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

[2] Rady Childrens Hosp, Rady Childrens Inst Genom Med, San Diego, CA 92123 USA

[3] Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA

[4] Rutgers State Univ, New Jersey Med Sch, Ctr Immun & Inflammat, Newark, NJ USA

[5] Univ Wisconsin, Dept Chem & Biol Engn, Madison, WI USA

[6] Univ Wisconsin, Dept Neurol Surg, Madison, WI USA

[7] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA

来源：

NATURE MEDICINE | 2021年 / 27卷 / 09期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

CHOROID-PLEXUS; BRAIN; PERICYTES; CELLS;

D O I：

10.1038/s41591-021-01443-1

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Findings from a pericyte-containing cortical organoid model suggests that pericytes provide an infection portal for SARS-CoV-2 and can serve as a viral amplification hub within neural tissue. Clinical evidence suggests the central nervous system is frequently impacted by SARS-CoV-2 infection, either directly or indirectly, although the mechanisms are unclear. Pericytes are perivascular cells within the brain that are proposed as SARS-CoV-2 infection points. Here we show that pericyte-like cells (PLCs), when integrated into a cortical organoid, are capable of infection with authentic SARS-CoV-2. Before infection, PLCs elicited astrocytic maturation and production of basement membrane components, features attributed to pericyte functions in vivo. While traditional cortical organoids showed little evidence of infection, PLCs within cortical organoids served as viral 'replication hubs', with virus spreading to astrocytes and mediating inflammatory type I interferon transcriptional responses. Therefore, PLC-containing cortical organoids (PCCOs) represent a new 'assembloid' model that supports astrocytic maturation as well as SARS-CoV-2 entry and replication in neural tissue; thus, PCCOs serve as an experimental model for neural infection.

引用

页码：1600 / +

页数：22

共 44 条

[1] Pericytes regulate the blood-brain barrier [J].