November 16, 2021

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by: admin

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Tags: accuracy, brain, cells, immune, improves, including, models, organoids, Spectrum

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Categories: autism

Together with immune cells in mind organoids improves mannequin’s accuracy | Spectrum

Subdued response: Organoids with microglia (bottom) show a lower interferon response (red) than organoids without microglia (top), suggesting that these immune cells help reduce cell stress.

Adding non-neural brain cells called microglia to cortical organoids speeds up the rate of maturation of their neurons, increases the synchronization of their firing, and appears to reduce cellular stress, according to a new study. These and other changes help the clusters of cultured cells more faithfully reflect how the human brain develops and functions, says the team behind the work. The researchers presented the results virtually at the Society for Neuroscience’s annual meeting in 2021.

Brain organoids grown from stem cells don’t always contain cells other than neurons – like astrocytes and microglia. In fact, the gene expression patterns of cells in organoids do not match those of human microglia, as earlier work shows.

“Microglia, or any immune cell population, are one of the most important cell types that are normally absent from organoids,” says Galina Popova, a postdoctoral fellow in the laboratory of Tomasz Nowakowski, assistant professor of anatomy at the University of California. San Francisco.

Under normal circumstances, microglia roam the central nervous system, looking for infections, and mopping up dead and dying cells. They also cut connections between neurons, a process that appears to be disrupted in autism.

Adding microglia to organoids of the brain is like adding a new brick shape to a Lego set, which makes it possible to more accurately model the microenvironment of the brain in the laboratory, says Popova. The cells could be the “missing link” between immune activation and the resulting changes that can contribute to autism, she adds.

“As the neuro-immune interaction gets more and more attention in modeling any brain development, it is really important – early or not – to consider the interaction between immune cells and other cell populations,” she says.

Relaxation:

Popova and her team induced the development of human skin cells into neurons, which then organized themselves into brain organoids in laboratory dishes. After the organoids had developed for 15 weeks, the team added microglia that were extracted from fetal brain tissue.

Five weeks later, electrophysiological tests showed that the neurons in the organoids with transplanted microglia fired with significantly greater synchronicity than those in the control organoids. Gene expression patterns also showed that these neurons matured faster.

RNA sequencing revealed some subtle differences in transcription between the microglial-containing organoids and the controls. In radial glial cells, a type of immature neural cell, the presence of microglia has been associated with a decrease in the expression of genes associated with viral immune responses. Radial glia in the microglia-containing organoids also showed fewer double-stranded DNA breaks, as shown by cell staining. Taken together, these results suggest that microglia reduce cell stress in the organoid environment – something that can affect cell specification, Popova says.

All of these processes associated with microglia indicate that they are critical to creating model organoids that accurately capture the brain environment, says Nowakowski.

The team is using this model, which they detailed in Cell Stem Cell in September, to study how microglia might protect the developing brain from certain gene mutations and environmental factors, including prenatal infections. They are also investigating how reactions or activation of microglia could impair the protective function of the cells, says Nowakowski.

Read more reports from the Society for Neuroscience’s 2021 Annual Virtual Meeting.

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