Modeling Human Cytomegalovirus-Induced Microcephaly in Human iPSC-Derived Brain Organoids

Cell Reports Medicine
Guoqiang SunYanhong Shi

Abstract

Although congenital infection by human cytomegalovirus (HCMV) is well recognized as a leading cause of neurodevelopmental defects, HCMV neuropathogenesis remains poorly understood. A major challenge for investigating HCMV-induced abnormal brain development is the strict CMV species specificity, which prevents the use of animal models to directly study brain defects caused by HCMV. We show that infection of human-induced pluripotent-stem-cell-derived brain organoids by a "clinical-like" HCMV strain results in reduced brain organoid growth, impaired formation of cortical layers, and abnormal calcium signaling and neural network activity. Moreover, we show that the impeded brain organoid development caused by HCMV can be prevented by neutralizing antibodies (NAbs) that recognize the HCMV pentamer complex. These results demonstrate in a three-dimensional cellular biosystem that HCMV can impair the development and function of the human brain and provide insights into the potential capacity of NAbs to mitigate brain defects resulted from HCMV infection.

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Citations

Oct 7, 2020·Brain : a Journal of Neurology·Polyxeni NikolakopoulouAnna Herland
Nov 17, 2020·Frontiers in Cellular and Infection Microbiology·Viviane Souza de CamposDaniel Adesse
Feb 3, 2021·International Journal of Molecular Sciences·Henkie Isahwan Ahmad Mulyadi LaiYi-Ping Yang
Jan 16, 2021·Cell Stem Cell·Cheng WangYanhong Shi
May 27, 2021·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·Jing-Han NgEng-King Tan
Jul 13, 2021·Frontiers in Molecular Biosciences·Kseniia Sarieva, Simone Mayer
Aug 6, 2021·Brain, Behavior, and Immunity·Amalie C M CouchAnthony C Vernon
Aug 28, 2021·Biology·Philip Jalink, Massimiliano Caiazzo

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Datasets Mentioned

BETA
GSE145415

Methods Mentioned

BETA
RNA seq
Assay
RNA-seq

Key Resources (RRID) Mentioned

Addgene_11011
Addgene_23892

Software Mentioned

ImageJ
TopHat2
ClustVis
NeuralMetric Tool
MEA
Pro Premier
Axion Biosystems NeuralMetrics Tool
Excel
AxIS
Prism

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