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Updated: Apr 20, 2026
Isolation and Direct Neuronal Reprogramming of Mouse Astrocytes
Published on: July 7, 2022
Human glial chimeric mice reveal astrocytic dependence of JC virus infection
Abstract:
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease triggered by infection with the human gliotropic JC virus (JCV). Due to the human-selective nature of the virus, there are no animal models available to investigate JCV pathogenesis. To address this issue, we developed mice with humanized white matter by engrafting human glial progenitor cells (GPCs) into neonatal immunodeficient and myelin-deficient mice. Intracerebral delivery of JCV resulted in infection and subsequent demyelination of these chimeric mice. Human GPCs and astrocytes were infected more readily than oligodendrocytes, and viral replication was noted primarily in human astrocytes and GPCs rather than oligodendrocytes, which instead expressed early viral T antigens and exhibited apoptotic death. Engraftment of human GPCs in normally myelinated and immunodeficient mice resulted in humanized white matter that was chimeric for human astrocytes and GPCs. JCV effectively propagated in these mice, which indicates that astroglial infection is sufficient for JCV spread. Sequencing revealed progressive mutation of the JCV capsid protein VP1 after infection, suggesting that PML may evolve with active infection. These results indicate that the principal CNS targets for JCV infection are astrocytes and GPCs and that infection is associated with progressive mutation, while demyelination is a secondary occurrence, following T antigen-triggered oligodendroglial apoptosis. More broadly, this study provides a model by which to further assess the biology and treatment of human-specific gliotropic viruses.
Insights
Researchers created a mouse model for progressive multifocal leukoencephalopathy (PML) by humanizing mouse white matter. This model shows JC virus (JCV) infects astrocytes and glial progenitor cells, leading to PML pathogenesis.
Area of Science:
- Neuroscience
- Virology
- Immunology
Background:
- Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease caused by the human-specific JC virus (JCV).
- The lack of animal models for JCV infection hinders research into its pathogenesis and treatment development.
Purpose of the Study:
- To develop a novel animal model for studying JC virus pathogenesis and PML.
- To investigate the cellular targets and mechanisms of JCV infection in the central nervous system.
Main Methods:
- Human glial progenitor cells (GPCs) were engrafted into neonatal immunodeficient and myelin-deficient mice to create humanized white matter.
- Intracerebral inoculation of JC virus (JCV) was performed in these chimeric mice.
- Infected tissues were analyzed for viral presence, replication, cellular tropism, and host cell responses, including apoptosis and viral mutation.
Main Results:
- The humanized mice developed JCV infection and demyelination, successfully modeling PML.
- JC virus primarily infected human astrocytes and GPCs, with viral replication observed in these cells.
- Oligodendrocytes showed T-antigen expression and apoptotic death, indicating secondary involvement in demyelination.
- Progressive mutations in the JCV capsid protein VP1 were observed during infection.
Conclusions:
- Astrocytes and GPCs are the principal central nervous system targets for JCV infection.
- Astroglial infection is sufficient for JCV propagation, and demyelination is a secondary consequence of oligodendroglial apoptosis.
- This humanized mouse model provides a valuable platform for studying human-specific gliotropic viruses like JCV and for developing therapeutic strategies.
