Organoids “fix” rat brains

This image shows a human brain organoid (green) implanted in a rat brain. © Jgamadze et al.

Implants of a special kind: Units of neurons grown in the laboratory could one day repair damage to human brains, according to successful animal experiments. A team of researchers was able to show that brain organoids grown from human induced stem cells can "mend" experimental injuries in the visual center of rats: the transplants networked and even reacted to visual impressions.

A fascinating technology has found its way into brain research in recent years: In order to clarify various questions about our thinking organ, to test drugs or for other medical purposes, scientists grow structures from neurons in the laboratory. These organoids, also known as "mini-brains", develop tissue structures and rudimentary reaction abilities that are similar to those of their role models. The brain organoids can also be cultivated from so-called induced pluripotent stem cells (iPS). These are stem cells that have been produced from mature body cells through certain treatments. For example, skin cells can reflect the ability to produce different types of tissue.

Replacement for lost nerve tissue?

The technology has also raised hopes that neuronal organoids can be used to repair damage to the brain, such as that caused by injuries or strokes. One could therefore develop neuronal organoids from a patient's iPS and then insert them in the affected area in the brain so that they can replace functions of the lost tissue there. The current study by the researchers led by senior author Isaac Chen from the University of Pennsylvania in Philadelphia is dedicated to this vision of the future. They have now explored the potential of this process in an animal model for the first time.

For their study, the scientists first grew neuronal organoids from human iPS. They were equipped with a fluorescence gene so that the nerve tissue can be made visible. Then, the resulting structures obtained were implanted into the brains of rats. The scientists had previously removed tissue from the target areas in the visual cortex of the animals. So, in principle, the organoid implants should fill these experimental injury gaps. In order to prevent rejection reactions against human tissue, the immune system of the animals was suppressed with medication.

Successfully integrated

As the team reports, the examinations of the brains of the test animals after three months revealed that the organoids had successfully integrated into the surrounding brain tissue. Blood vessels had formed and the neurons also seemed to have "wired themselves in". Exactly nThe researchers were able to prove this using a method in which fluorescent fours are used, which propagate along neuronal connections. The researchers injected these viral tracers into the retina of the test animals and were then able to use the propagation pattern to understand how far the transsynaptic networks reach from the eye. It turned out: “The tracer actually got to the organoid. This made the successful neural connection of the implant clear,” says Chen.

Through further experiments, the researchers were then able to show that the nerves in the integrated organoid even react to visual stimuli. They were able to demonstrate this using fine electrode probes that were inserted into the implants. When the test animals were then confronted with flashing lights or alternating white and black bars, specific reactions in the neurons of the organoids became apparent: “We saw that a large number of neurons within the organoid responded to specific light alignments. This made it clear that the implants had not only integrated into the visual system, but could even take over functions of the visual cortex,” explains Chen.

The team now sees this as a promising step on the way to using organoid technology as a healing method. "Neural tissues do appear to have the potential to rebuild areas of the injured brain," Chen said. He and his team now want to stay on the ball: “We plan to explore how organoids could be used in other areas of the brain. We also want to investigate the rules according to which organoid neurons integrate into the brain so that we can better control and accelerate this process," says the scientist.

Source: University of Pennsylvania, professional article: Cell Stem Cell, doi: 10.1016/j.stem.2023.01.004

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