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Asian Scientist Magazine (Dec. 19, 2023) —Brain organoids or mini-brains grown in the lab have furthered our understanding of the human brain in recent years. Scientists culture them to study how the brain develops, screen drugs, and create advanced neural networks. These organoids, however, are usually limited by a lack of cell types other than neurons.
Brain organoids that lack other cell types miss out on the interactions between neurons and other cells. For example, microglia are a class of immune cells that lay the foundation for the growing brain and facilitate maintenance and repair throughout life. How the microglia interact with the developing brain remains a mystery because of the lack of tools to study them.
In a multi-institutional effort led by the Singapore Immunology Network (SIgN), researchers devised a protocol to introduce microglia in brain organoids. The study published in the journal Nature showed that the microglia helped nerve cells in brain organoids reach their full potential.
“We have produced neuronal organoids with microglia by cultivating together organoids and primitive-type macrophages, generated from the same culture of induced pluripotent stem cells,” said Florent Ginhoux, a SIgN researcher and the corresponding author of the study.
Induced pluripotent stem cells are embryo-like cells generated by reprogramming mature skin or blood cells back into a native state. When cultured next to each other, the macrophages moved into the organoids where they differentiated into microglia. These microglia-enriched organoids mimicked the processes that occur in the embryonic brain.
Interestingly, organoids with microglia were smaller in size than those without. They also had fewer neuronal progenitor cells, stem cells that give rise to both nerve cells and microglia. This showed that microglia reduce the proliferation of these progenitor cells, instead pushing them to differentiate into specialized cells.
They had greater expression of genes involved in producing nerve cells and outlining the nervous system. The microglia-enriched organoids were also more mature as this promoted the growth of synapses and axons. Neurons have long extending fibers called axons and synapses that connect neurons, both helping signals to move from one neuron to the next. The neurons in organoids fired at a rate higher than in organoids lacking microglia.
Next, the team looked at cholesterol levels in these organoids. The brain makes its cholesterol and has the highest cholesterol level of all organs in the body. It is known to protect neurons and ensure their proper functioning. The researchers found that microglia regulated metabolic pathways that store and transport cholesterol. Lipid-like droplets in microglia carried cholesterol, which was then picked up by other cell types.
This cholesterol exchange was crucial to the maturation of the organoids. “The neural progenitor cells that absorb this cholesterol undergo metabolic reprogramming as they differentiate into nerve cells,” said Ginhoux.
When this exchange process was blocked, the organoids were larger, like organoids without microglia. This proved that cholesterol exchange facilitated the maturation of neuronal progenitor cells. More importantly, it hinted at a mechanism to tackle several neurological conditions, including Alzheimer’s and Parkinson’s.
Disruptions in cholesterol levels have been implicated in the onset of these diseases. Scientists suspect that many neurological disorders that appear later in life may have subtle origins in brain development in the embryos. The links between these diseases, cholesterol levels in the brain, and microglia metabolism have been underexplored.
Microglia-enriched brain organoids provide a window to bridge this gap and develop effective treatments. “This will enable us to study the role of microglia in the setting of diseases and suggest ways to develop new therapies,” said Ginhoux.
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Source: Singapore Immunology Network (SIgN); Image: Shutterstock
The paper can be found at: iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer | Nature
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.
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