Scientists at Pennsylvania State University (Penn State) in State College converted glial cells into functioning neurons by using a combination of just four small molecules.
Glial cells, among other things, can support and protect neurons, which are cells that perform the mental functions of the brain.
In a new study paper that now features in the journal Stem Cell Reports, the researchers describe how their converted neurons survived for more than 7 months in laboratory cultures.
The new neurons also showed an ability to work like normal brain cells. They formed networks and communicated with each other using both electrical and chemical signals.
Glial cells proliferate after injury
Senior study author Gong Chen, who is a professor of biology at Penn State, explains that neurons do not regenerate when brain tissue becomes damaged.
“In contrast,” he adds, “glial cells, which gather around damaged brain tissue, can proliferate after brain injury.”
In their study paper, he and his team explain how glial cells form scars that protect the neurons from further injury.
However, due to their constant presence, glial scars also block the growth of new neurons and the transmission of signals between them.
Previous attempts to restore neuron regeneration by removing the glial scars have had “limited success,” note the study authors.
Prof. Chen believes that “the best way to restore lost neuronal functions” is to create new neurons out of the glial cells close to the dead neurons.
Reprogramming astrocytes into neurons
In previous work, Prof. Chen and his team had shown that it was possible to “chemically reprogram” a type of glial cell called astrocytes into neurons using nine small molecules in a certain sequence. However, when they explored how to translate the method from the laboratory to the clinic, they realized that it was too complicated.
So, the aim of the new study was to find a smaller combination of the molecules that can reprogram astrocytes into functioning neurons in a more straightforward way.
The researchers tested hundreds of combinations until they found an effective formula comprising “four core drugs.”
“By using four molecules,” explains first study author Jiu-Chao Yin, who is a graduate student in biology at Penn State, “that modulate four critical signaling pathways in human astrocytes, we can efficiently turn human astrocytes — as many as 70 percent — into functional neurons.”
The team also tested the effect of dropping one of the four molecules from the formula. No three-drug formula, however, was as effective as the four-drug version. In fact, the best three-drug combination was 20 percent less effective than the four-drug one.
Using only one of the molecules was not enough to convert the astrocytes into neurons.
Simple alternative to gene therapy
Prof. Chen and his colleagues have been working on regenerating neurons for some time. Before turning to chemical reprogramming, they had experimented with gene therapy.
However, they concluded that a gene therapy approach, which could cost around $500,000 per person, would be too expensive. In addition, delivery of gene therapy requires sophisticated, advanced techniques and expertise.
Prof. Chen explains that the main advantage of the chemical programming approach is that “a pill containing small molecules could be distributed widely in the world, even reaching rural areas without advanced hospital systems.”
Also, he and his team found that injecting the four drugs into adult mice increased the generation of new brain cells in the hippocampus, which is a region of the brain that plays a role in memory.
A lot more work ahead
The study authors point out that the findings are just one step forward toward neuron regeneration in a pill. There is still a lot of work to do in developing the right formula, particularly regarding the “packaging and delivery” of the small molecules.
As well as confirming their effectiveness, the researchers also need to explore the side effects and safety of the drugs.
They are confident, however, that their new four-drug formula will one day realize its potential as a straightforward treatment for people who lose neuronal function through brain injury, stroke, and neurodegenerative conditions such as Alzheimer’s disease.
“My ultimate dream is to develop a simple drug delivery system, like a pill, that can help stroke and Alzheimer’s patients around the world to regenerate new neurons and restore their lost learning and memory capabilities.”
Prof. Gong Chen
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