Human brain organoids in mice give first glimpse of microglia dysfunction in autism

Another day, another Frankenmouse: Scientists have once again implanted human-derived organoids into mouse brains, in this case to study the brain’s immune cells in-depth for the first time.

In a study published May 11 in Cell, a research team led by scientists from the Salk Institute described how they developed a new mouse model containing organoids grown from human brain tissue. They then gave it a whirl to show how microglia—the brain’s resident immune cells—have unique development patterns in the brains of people with autism.

“Mounting evidence from human and animal studies suggests that microglia may be implicated in various brain disorders, including neurodevelopmental conditions such as autism spectrum disorder,” the scientists wrote in the paper. “However, until now, the ability to model interactions between human brain cells and microglia has been severely limited.”

It’s challenging to study microglia in a cell culture alone because their form and function is dictated by the neural environment. Outside the brain, they take on a partially-activated state that doesn’t reflect their gene expression profile or behavior in their typical ecosystem.

Human brain organoids alone don’t solve the problem, as the researchers explained in their paper. While the “miniature organs'' do recapitulate the brain’s 3D structure and many of its cell types, that doesn’t include microglia. That’s because microglia don’t come from the ectoderm, a precursor to embryonic stem cells that gives rise to the central nervous system.

To get around that, the team first grew brain organoids from human stem cells. They then transplanted the organoids into the forebrains of mice, where they formed blood vessels and integrated themselves into the surrounding tissue. Next, the researchers added human erythromyeloid progenitors, precursor cells to microglia, into the organoids.

By tracking gene and protein expression, the scientists found that the progenitor cells developed into mature microglia just as would be expected in the brain. They also noted the presence of environment-specific factors that were necessary for the microglia to proliferate and function, rounding out a model that accurately mirrored the way microglia grow and behave in the brain.

To put their new model to the test, the researchers set out to learn if neurons derived from people with autism influenced the brain microenvironment and the development of microglia. They grew the cells from two sets of skin samples: One from three individuals with macrocephalic autism spectrum disorder—a form of autism that’s accompanied by macrocephaly, a condition where the head is larger than normal—and another from three individuals with macrocephaly alone.

Studies on tissue from the models showed that the tissue grown from neurons from people with autism caused the transplanted microglia to exhibit unique gene expression patterns that made them more reactive, driving inflammation. The microglia by themselves didn’t have the same patterns, suggesting the changes were influenced by the surrounding neural environment—and not something intrinsic to the microglia. This finding supported what researchers have seen in post-mortem studies on the brains of people with autism, which have shown higher levels of inflammation.

The model has some limitations, the scientists noted in their paper. For one, they’ll need to understand how much cells from the mouse brain are contributing to the neural environment in the human tissue. They need to conduct more in-depth studies to see if blood vessels that integrate the human tissue into the mouse brain are a product of the host cells alone, or if the human cells have a part in their development too.

As for the relationship between microglia and the neural environment in patients with autism, the researchers will need to see if their findings hold up in studies with larger sample sizes. They also plan to use their model to study microglias’ role in other developmental conditions as well as neurodegenerative diseases like Alzheimer’s, a press release from the Salk Institute said.

Human organoids transplanted into rodent brains have become increasingly common in research settings, as scientists look for new ways to study the organ’s function in an in-depth way that’s not possible with human subjects. In February, scientists from the University of Pennsylvania demonstrated that human brain organoids in mice with visual injuries could react to light. And in October 2022, a Stanford team announced that the human neurons they wired into rats' brains were capable of learning, as shown in experiments where the rats learned to drink water in response to a stimulus.