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Updated: Nov 29, 2025
Generation of iPSC-derived Human Brain Organoids to Model Early Neurodevelopmental Disorders
Published on: April 14, 2017
Modeling Human Cytomegalovirus-Induced Microcephaly in Human iPSC-Derived Brain Organoids
Guoqiang Sun1, Flavia Chiuppesi2, Xianwei Chen1
1Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA.
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.
Insights
Human cytomegalovirus (HCMV) infection impairs brain development in organoids, causing growth reduction and abnormal neural activity. Neutralizing antibodies targeting the HCMV pentamer complex can prevent these defects.
Area of Science:
- Neuroscience
- Virology
- Developmental Biology
Background:
- Congenital human cytomegalovirus (HCMV) infection is a primary cause of neurodevelopmental deficits.
- The mechanisms of HCMV neuropathogenesis are not fully understood.
- Species specificity of HCMV hinders direct study in animal models.
Purpose of the Study:
- To investigate the effects of HCMV on human brain development using a novel in vitro model.
- To explore the potential of neutralizing antibodies (NAbs) in mitigating HCMV-induced brain abnormalities.
Main Methods:
- Utilized human-induced pluripotent stem cell-derived brain organoids.
- Infected organoids with a clinical-like HCMV strain.
- Assessed organoid growth, cortical layer formation, and neural network activity.
- Evaluated the efficacy of NAbs targeting the HCMV pentamer complex.
Main Results:
- HCMV infection led to reduced brain organoid growth and impaired cortical layer development.
- Abnormal calcium signaling and neural network activity were observed in infected organoids.
- NAbs targeting the HCMV pentamer complex successfully prevented HCMV-induced developmental deficits.
Conclusions:
- HCMV can directly impair human brain development and function in a three-dimensional cellular system.
- Neutralizing antibodies offer a potential therapeutic strategy to mitigate HCMV-related brain defects.
