If neurons could be replaced, neuronal deficits caused by Alzheimer’s disease, stroke, or brain injury could be reversed. Unfortunately, neurons refuse to divide. New neurons, then, must come from somewhere else—or rather something else. One potential something else is the astrocyte. Not only do astrocytes proliferate after brain injury, these cells, which normally support and insulate neurons, can be reprogrammed so that they become neurons themselves.
But there’s a problem: astrocyte-to-neuron reprogramming is difficult. Existing reprogramming approaches, which include gene therapy and chemical conversion, are costly, complex, or both. Gene therapy, for example, requires that genes be delivered into the human body by viral particles. Also, gene therapy is costly—up to half a million dollars per patient.
Chemical conversion can be complicated, too. For example, a chemical conversion technique developed by researchers at Penn State makes use of a cocktail of nine small molecules. A nine-molecule recipe, the Penn State team acknowledges, is difficult for clinical applications.
The Penn State team, however, is loath to admit defeat. Under the leadership of Gong Chen, PhD, professor of biology, the team developed a simpler cocktail. It can chemically convert astrocytes to functional neurons using just four small molecules, or even just three, if less efficiency can be tolerated.
Details about the new cocktail appeared February 7 in Stem Cell Reports, in an article titled, “Chemical Conversion of Human Fetal Astrocytes into Neurons through Modulation of Multiple Signaling Pathways.”
“We demonstrate that modulation of three to four signaling pathways among Notch, glycogen synthase kinase 3, transforming growth factor β, and bone morphogenetic protein pathways is sufficient to change an astrocyte into a neuron,” the article’s authors wrote. “The chemically converted human neurons can survive >7 months in culture, fire repetitive action potentials, and display robust synaptic burst activities.”
The chemically converted neurons not only survive for months in a culture dish in the lab, they also form robust neural networks and send chemical and electrical signals to each other, as normal neurons do inside the brain.
When administered in vivo through intracranial or intraperitoneal injection, the four-drug combination can significantly increase hippocampal neurogenesis in adult mice, the article’s authors added.
“We identified the most efficient chemical formula among the hundreds of drug combinations that we tested,” said Jiu-Chao Yin, a graduate student in biology at Penn State who identified the ideal combination of small molecules. “By using four molecules that modulate four critical signaling pathways in human astrocytes, we can efficiently turn human astrocytes—as many as 70%—into functional neurons.”
Using three of the small molecules instead of four also results in the conversion of astrocytes into neurons, but the conversion rate drops by about 20%. The team also tried using only one of the molecules, but this approach did not induce conversion.
“The most significant advantage of the new approach is that a pill containing small molecules could be distributed widely in the world, even reaching rural areas without advanced hospital systems,” said Chen. “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.”
The researchers acknowledge that many technical issues still need to be resolved before a drug using small molecules could be created, including the specifics of drug packaging and delivery. They also plan to investigate potential side effects of this approach in future studies in order to develop the safest drug pills. Nonetheless, the research team is confident that this combination of molecules has promising implications for future drug therapies to treat individuals with neurological disorders.
“Our years of effort in discovering this simplified drug formula take us one step closer to reaching our dream,” said Chen.