UT Southwestern Researchers Report Reprogramming Common Brain Cells into Neurons that Form Networks

UT Southwestern Medical Center researchers report reprogramming the most common non-neuronal brain cells in mammals into precursor cells that grew into functioning neural networks in mice.

The first proof-of-concept study in mammals indicates it may someday be possible to regenerate neurons to treat traumatic brain injuries or central nervous system (CNS) disorders like Alzheimer’s disease, using a patient’s own, fully differentiated adult cells, thereby avoiding the need for stem cell transplants, the researchers report in the October edition of Nature Cell Biology.

Dr. Chun-Lu Zhang and Dr. Wenze Niu
Senior author Dr. Chun-Li Zhang, left, and lead author Dr. Wenze Niu. 

“We have identified a simple approach to create new neuronal precursors and mature neurons from native astrocytes (common brain cells that are involved in many functions such as metabolism and scar formation) in the adult mouse brain,” said senior author Dr. Chun-Li Zhang, an assistant professor of molecular biology at UT Southwestern.

“Our work is the first to clearly show in vivo (in a living model) that mature astrocytes can be reprogrammed to become functional neurons without the need of cell transplantation. These results could open new ways for regeneration-based therapy using a patient’s own native cells,” he added.

The researchers also reported that mice followed for nearly a year after the procedure showed no signs of tumor growth. Tumorigenesis is a concern when cells are reprogrammed to an earlier stage of development as were the mature astrocytes in this study, Dr. Zhang explained.

“Our ability to generate proliferating non-tumorigenic neuroblasts from resident astrocytes is a milestone in our pursuit of regeneration-based cell therapies for the treatment of CNS-associated injuries or diseases,” the researchers wrote in their conclusion.

“Neuron loss is a frequent result of head injury or degenerative disease. A fundamental but unresolved challenge is how to create new neurons for potential repair of the damaged neural circuits, since new neurons are rarely generated once the brain is formed,” Dr. Zhang said. He explained that the brain has limited regeneration ability and neuroblasts have been identified only in two small areas of the brain. Astrocytes, in contrast, are widely disbursed throughout brain tissue, making them an ideal candidate for regenerative medicine based on their location, he said.

Lead author Dr. Wenze Niu, a research scientist in molecular biology, said that a single transcription factor, SOX2, was enough to transform mature astrocytes in the brain into nerve progenitor cells (neuroblasts). However, those neuroblasts could not survive or mature without another step.

Next, the researchers introduced the neuroblasts in the brain to several factors in a search for any that could make the brain environment more suitable for neuroblast survival and maturation. Their experiments identified three such factors: the growth factors BDNF and noggin and a histone deacetylase inhibitor, which is a drug used to treat epilepsy that is known to increase levels of BDNF, Dr. Zhang said.

Either the growth factors together or the epilepsy drug caused the neuroblasts to mature into neurons that incorporated into functioning neural networks, capable of delivering chemical messages across synapses, the scientific term for the gaps between neurons, the researchers explained.

The two-step process created new neurons in both young and old mice, although the response was about five times more robust in the younger adults, Dr. Zhang said.

“Our results demonstrate that adult astrocytes exhibit remarkable plasticity in vivo, a feature that might have important implications in regeneration of the CNS using a patient’s own resident glial cells, of which astrocytes are a subset,” Dr. Zhang said.

“We are very excited about these findings, which have completely changed our original views on regeneration-based therapy against neural injury or degeneration,” Dr. Zhang said.

However, he added that more research is needed to determine whether these mouse results will translate to humans.

UT Southwestern co-authors include postdoctoral fellow Dr. Tong Zang, research scientist Yuhua Zou, and former postdoctoral fellow Dr. Sanhua Fang, all of the department of molecular biology. Dr. Fang is now a lecturer at Zhejiang University in China. In addition, Derek Smith, a graduate student in the neuroscience program and in molecular biology; and Dr. Robert Bachoo, an assistant professor of neurology at UT Southwestern, participated in the research.

Funding: This research was supported by a National Institutes of Health Director’s New Innovator Award as well as by The American Heart Association, The Whitehall Foundation, The Welch Foundation Award, and The Ellison Medical Foundation Award.

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Dr. Zhang is the W.W. Caruth, Jr. Scholar in Biomedical Research.