Astroglial cells before (top) and after (bottom) treatment with small-molecule cocktails (credit: Gong Chen lab, Penn State University)
Researchers have succeeded in transforming human support brain cells, called astroglial cells, into functioning neurons for brain repair.
The new technology opens the door to future development of drugs that patients could take as pills to regenerate neurons and to restore brain functions lost after traumatic injuries, stroke, or diseases such as Alzheimer’s.
Previous research, such as conventional stem-cell therapy, has required brain surgery, so it is much more invasive and prone to immune-system rejection and other problems.
The new research, led by Gong Chen, Professor of Biology and the Verne M. Willaman Chair in Life Sciences at Penn State University, was published online today (Oct. 15) in the journal Cell Stem Cell.
“We have discovered a cocktail of small molecules that can reprogram human brain astroglial cells into neuron-like cells after eight to ten days of chemical treatment,” Chen said. The reprogrammed nerves survived for more than five months in cell culture, where they formed functional synaptic networks.
The scientists also injected the reprogrammed human neurons into the brains of living mice, where they integrated into the neural circuits and survived there for at least one month.
“The small molecules are not only easy to synthesize and package into drug pills, but also much more convenient for use by patients than other methods now being developed,” Chen said.
Converting astroglial cells into neurons
Astroglial cells surround neurons and provide them with support, protection, oxygen, and nutrients. But when brain tissues are damaged by strokes or trauma, the astroglial cells react by multiplying — sometimes so much that they clog up the nervous system by forming a scar. These astroglial scars — a difficult research challenge for many decades — can cause health problems by preventing nerve regeneration and by blocking nerve-to-nerve communications between different regions of the brain.
Chen’s group previously invented a method to convert astroglial cells into neurons using viral particles. But Chen also wanted to investigate whether small chemical compounds, which could be packaged into swallowable pills, could also do the job.
Five students on Chen’s research team, led by graduate student Lei Zhang, tested hundreds of different conditions and eventually identified a cocktail of small molecules that can convert human astroglial cells into functional neurons in a cell-culture dish in the laboratory. The students found that adding small molecules in a certain sequence transformed the cultured human astroglial cells from a flat, polygon shape into a neuron-like shape with long “arms” called axons and dendrites.
“These chemically generated neurons are comparable to normal brain neurons in terms of firing electric activity and release of neurotransmitters,” Chen said. “Importantly, the human astroglial-converted neurons survived longer than five months in cell culture and longer than one month in the living mouse brain after transplantation.”
Chen acknowledges that further development, laboratory testing, and a series of clinical trials are still required, but he hopes that this new technology may have broad applications in the future treatment of stroke, Alzheimer’s disease, Parkinson’s disease, and other neurological disorders.
“Our dream is that, one day, patients with brain disorders can take drug pills at home to regenerate neurons inside their brains without any brain surgery and without any cell transplantation,” he said.
Scientists from Emory University School of Medicine were also involved in the research.
Abstract of Small Molecules Efficiently Reprogram Human Astroglial Cells into Functional Neurons
We have recently demonstrated that reactive glial cells can be directly reprogrammed into functional neurons by a single neural transcription factor, NeuroD1. Here we report that a combination of small molecules can also reprogram human astrocytes in culture into fully functional neurons. We demonstrate that sequential exposure of human astrocytes to a cocktail of nine small molecules that inhibit glial but activate neuronal signaling pathways can successfully reprogram astrocytes into neurons in 8-10 days. This chemical reprogramming is mediated through epigenetic regulation and involves transcriptional activation of NEUROD1 and NEUROGENIN2. The human astrocyte-converted neurons can survive for >5 months in culture and form functional synaptic networks with synchronous burst activities. The chemically reprogrammed human neurons can also survive for >1 month in the mouse brain in vivo and integrate into local circuits. Our study opens a new avenue using chemical compounds to reprogram reactive glial cells into functional neurons.