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Published on: September 19, 2010
HIV-1 infection promotes neuroinflammation and neuron pathogenesis in novel microglia-containing cerebral organoids
Abstract:
Cerebral organoids (COs) are a valuable tool to study the intricate interplay between glial cells and neurons in brain development and disease, including HIV-associated neuroinflammation. We developed a novel approach to generate microglia containing COs (CO-iMs) by co-culturing hematopoietic progenitors and induced pluripotent stem cells. This approach allowed for the differentiation of microglia within the organoids concomitantly to the neuronal progenitors. CO- iMs exhibited higher efficiency in generation of CD45 + /CD11b + /Iba-1 + microglia cells compared to conventional COs with physiologically relevant proportion of microglia (∼7%). CO-iMs exhibited substantially higher expression of microglial homeostatic and sensome markers as well as markers for the complement cascade. CO-iMs showed susceptibility to HIV infection resulting in a significant increase in several pro-inflammatory cytokines/chemokines and compromised neuronal function, which were abrogated by addition of antiretrovirals. Thus, CO-iM is a robust model to decipher neuropathogenesis, neurological disorders, and viral infections of brain cells in a 3D culture system.
Insights
Researchers developed novel microglia-containing cerebral organoids (CO-iMs) to model brain development and HIV-associated neuroinflammation. These organoids accurately mimic human brain cells and their response to viral infection in a 3D system.
Area of Science:
- Neuroscience
- Stem Cell Biology
- Immunology
Background:
- Cerebral organoids (COs) are crucial for studying brain development and disease.
- HIV-associated neuroinflammation presents challenges in understanding brain cell interactions.
- Existing models lack sufficient glial cell representation.
Purpose of the Study:
- To develop a novel cerebral organoid model containing microglia (CO-iMs).
- To investigate the utility of CO-iMs in studying HIV neuropathogenesis.
- To assess the impact of HIV infection and antiretroviral therapy in a 3D brain model.
Main Methods:
- Co-culturing hematopoietic progenitors and induced pluripotent stem cells to generate microglia-containing COs (CO-iMs).
- Characterizing microglia differentiation and proportions within CO-iMs using specific cell markers (CD45, CD11b, Iba-1).
- Assessing microglial gene expression related to homeostasis, sensome, and complement cascade.
- Infecting CO-iMs with HIV to evaluate neuroinflammation and neuronal function changes.
- Testing the efficacy of antiretroviral drugs in mitigating HIV-induced effects.
Main Results:
- CO-iMs demonstrated efficient generation of microglia with a physiologically relevant proportion (∼7%).
- CO-iMs exhibited enhanced expression of microglial homeostatic, sensome, and complement cascade markers.
- HIV infection in CO-iMs led to increased pro-inflammatory cytokines/chemokines and impaired neuronal function.
- Antiretroviral treatment abrogated HIV-induced inflammatory responses and neuronal dysfunction in CO-iMs.
Conclusions:
- CO-iMs represent a robust 3D model for studying brain development and neuropathogenesis.
- This model is effective for investigating viral infections, such as HIV, in the brain.
- CO-iMs provide a platform for deciphering neurological disorders and testing therapeutic interventions.
