Understanding autism through organoids

In the brain, microglia ensure, among other things, that damaged nerve cells are destroyed and their remnants broken down. However, they can also promote the growth of neurones. As a result, they play an important role in the development of the brain, but also in diseases of the nervous system.

Much about the function of microglia is still unknown. One reason for this is that their behaviour under laboratory conditions is fundamentally different from that in the human body. An international research team, in which Simon Schäfer, Professor of Advanced Organoid Technologies for Mental Health Research at the Technical University of Munich (TUM), played a major role, describes a solution to this problem in the scientific journal „Cell“.

Microglia and organoid from stem cells

„Outside the brain, microglia lose almost all function”, says Prof Rusty Gage, last author of the study from the Californian Salk Institute. „We therefore recreate the environment of the brain in an organoid to study human microglia. This gives us a tool to study how the healthy and diseased brain influence the microglia – and vice versa, how healthy and diseased microglia influence the brain.“

On the one hand, the team developed a process to produce microglia from human pluripotent stem cells. On the other hand, the researchers also succeeded in producing an organoid about five millimetres in size from stem cells. Unlike previous brain organoids, this one can be used to recreate not only the early developmental phase of the brain, but also later stages. This is an important prerequisite for the study of diseases that only occur later in life.

A 3D cell system

„Organoids are often described as a kind of mini-version of an organ,

says Simon Schäfer. „In this case, however, that evokes the wrong associations. The brain is associated with consciousness, with sensations and thinking. Our organoids can never be capable of this - nor should they be.“ It is true that the organoids contain nerve cells that also communicate with each other, explains Schäfer. However, the networks of different areas that make thinking and consciousness possible in the first place are missing.

From a more basic point of view, we can speak of three-dimensional cell systems with which we recreate individual aspects of brain development,

says Schäfer.

Processes in the body imitated

As a next step, the team developed a method to implant the cultured microglia into organoids. The scientists are thus recreating another process in the development of our brain: Microglia do not migrate into the area that later becomes the brain until around the fifth week of pregnancy.

So far, however, the behaviour of microglia in organoids in the culture dish does not correspond to that in the human body. However, the team was able to insert the organoids into the body of mice. In a living organism, the microglia behaved like their counterparts in the brain. They proliferated and were able to eliminate damaged neurones of the organoid. „We are now working on finding out how we can get our organoids to behave in the culture dish as they do in the body“, says Simon Schäfer.

Organoids from cells of autistic patients

With the new organoid systems, the researchers hope to gain new insights into the development of the brain. On the other hand, they can help to better understand individual diseases: The scientists used skin cells from three patients with macrocephalic autism to generate stem cells, which in turn were used to generate organoids and microglia cells. Previous studies had shown that neurons and microglia behave unusually in this autism spectrum disorder. The team has now been able to show that these differences also occur in the organoids.

„Our experiments have shown that microglia in organoids from stem cells of patients react more aggressively to damaged cells than in organoids from cells of people from the control group,

says Simon Schäfer. The aggressive reaction also occurred when microglia from the stem cells of the control group were introduced into brain organoids from patients. Accordingly, the behaviour was apparently caused more by the microglia's environment than by their own properties. This could explain the origin of the inflammatory processes in the brain that frequently occur in this disease.

Brain, heart and pancreas as organoids

Simon Schäfer has been researching at TUM since 2022. His research group will be particularly involved in interdisciplinary research at the Centre for Organoid Systems. Research on brain organoids is one of the three core topics of the new centre. In recent months, other TUM teams have already presented highly acclaimed research results on pancreatic and cardiac organoids 

.

„At TUM, we will continue to develop the brain model in order to find new connections between the brain and the immune system,

says Simon Schäfer. „In addition, we want to develop approaches from the stem cell-induced glial cells to repair or replace the affected tissue in the event of brain damage.“

Source: Press release Technische Universität München from 22 May 2023