Making “New” Neurons for Recovery After Brain Injury

A brain of newborn mice: astrocytes are depicted in red, and cell nuclei are depicted in blue. Photo: Archontia Kaminari via CC BY-SA 4.0.

One of the most intriguing developments in the so-called golden age of neuroscience has been the growing understanding of “neuroplasticity”: the brain’s ability to constantly reshape itself and constantly learn new things by forging new connections throughout one’s lifetime — to grow proportions of gray matter and even shift brain activity to different regions of the brain.

Now a new research effort is taking the concept of neuroplasticity further — looking at diseased and injured brains that have permanently lost neurons. The effort, led by neuroscientist Magdalena Götz, explores whether “astrocytes” — non-neuronal, structural cells in the brain, can be reprogrammed to take up the tasks the neurons once performed.

“Everybody is astonished, at the moment, that it works,” says Nicola Mattugini, a neurobiologist at the Ludwig Maximilian University of Munich, Germany, when she presented her team’s results at the annual meeting of the Society for Neuroscience in San Diego, California. Their team reprogrammed the astrocytes in lab mice.

There are further questions to explore — whether the newly built neurons indeed function the same way as their lost counterparts, and whether it’s a good idea to create neurons while extracting astrocytes from brain-damaged animals. Many researchers do not share Mattugini’s optimism. Along with two other groups, they presented evidence during the conference that these reprogrammed astrocytes can successfully take on the duties of the neurons they’re intended to replace, to some degree. The other teams offered further evidence to suggest the reprogrammed astrocytes can even help mice regain some motor control after suffering from strokes.

Supporters of their research see this approach as an alternative to stem cell transplants, or of using neurons grown from stem cells — treatments already undergoing trials for disorders like Parkinson’s. Gong Chen, a neuroscientist at Pennsylvania State University, walked away from the conference with some renewed optimism. He had previously conducted a similar experiment, where the transplanted cells in his mice produced relatively few neurons that were not fully functional. Learning that matured cells can be repurposed suggested the way to a better approach.

The astrocytes, known for their star shape, are a type of glial cell in the brain — named because they were long thought to be the “glue” of the brain’s structure, little more than a type of connective tissue. We now know this is not the case — that glial cells provide nutrients to neurons and help to regulate blood flow, sometimes even interacting with them. In the event of an injury, they multiply and promote inflammation, with healing effects debated to be both helpful and harmful to the individual.

Chen’s team injected a harmless virus into the rodent’s brain to act as an envelope. When the virus “infected” local astrocytes, it released a set of instructions in the form of DNA, signaling the host astrocyte to activate the genes commonly expressed in neurons. This mutation signaled the other astrocytes to multiply nearby — and could be the reason that the treatment does not deprive the brain of the astrocytes it needs.

All three groups still have to demonstrated that these reprogrammed cells can be wired up into the brain’s circuits to carry out the tasks of missing neurons — but there is evidence that the astrocytes take on key neural features when they drop their feathery tendrils. Instead, they produce neural proteins and new fibers that reach across the brain, toward the spinal cord. The reprogrammed cells even appear to relay electrical signals, like neurons.

Chen has established a company to focus on therapies that reprogram astrocytes, exploring the possibility of using a molecular cocktail to signal production, in light of invasive surgery or a passenger virus. “I believe this is the future,” he said as he presented his findings. “It’s the next frontier in regenerative medicine.”

A few researchers are already following their lead. Another effort last year by Swedish scientists restored motor function in a mouse model of Parkinson’s disease. They reprogrammed the astrocytes into neurons that could produce the neurotransmitter dopamine. Stem cell biologist Maryam Faiz of the University of Toronto injected the protein NeuroD1 into mice that had suffered a stroke, and found they recovered more quickly than the untreated control group. After two months, they performed as well as healthy mice on walking tests.

For her colleague, Cindi Morshead, this is a sign of great promise for the future — particularly when it comes to humans disabled chronically from the effects of a stroke. For these individuals, there are few treatment options available. Morshead hopes that a future trial could show that mice long disabled by a stroke benefit from newly grown neurons — opening the gateway to treating long-suffering patients.

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