Reprogramming of glial cells for the treatment of CNS diseases

Researchers at the University of Pennsylvania, working under the leadership of Professor Gong Chen, have developed a new technology for restoring functional brain neurons using glial cells – auxiliary cells of the central nervous system. The authors believe that their development can be taken as a basis for new therapeutic approaches to the treatment of traumatic brain and spinal cord injuries, strokes, Alzheimer's and Parkinson's diseases and other diseases of the central nervous system.

When the brain is damaged as a result of injury or illness, neuronal death or degeneration often occurs, which is accompanied by an increase in the number and branching of glial cells. Initially, such "reactive glial cells" form a defense system that prevents the penetration of bacteria and toxins into healthy nerve tissue, but eventually this leads to the formation of glial scars that interfere with the growth of new neurons.

A few years ago, the authors, inspired by the Nobel Prize-winning technology for converting mature skin cells into induced pluripotent stem cells, began work on a method for converting glial scars into normally functioning nerve tissue.

First, they studied the reaction of reactive glial cells to a specific protein NeuroD1, known for its important role in the formation of new nerve cells in the hippocampus of the adult brain. They suggested that the expression of NeuroD1 by reactive glial cells in the damaged area may provide the formation of new neurons. To test this hypothesis, the researchers injected a modified retrovirus containing the NeuroD1 protein gene into glial cells. This virus is not capable of killing cells, moreover, it infects only dividing cells, which makes it tropic exclusively to reactive glial cells. This eliminates the possibility of infection of neurons and minimizes the possible negative impact on the brain.

As part of the first experiment, the authors studied the possibility of converting reactive glial cells into functional neurons after the introduction of the NeuroD1 retrovirus gene into the cerebral cortex of adult mice. A week after the introduction of the viral vector, an analysis of animal brain tissue showed that two types of glial cells – stellate astroglial cells and NG2 cells – successfully transformed into neurons. At the same time, it turned out that astroglial cells gave rise to excitatory, and NG2 cells gave rise to both excitatory and inhibitory neurons. According to Chen, this allows us to achieve a balance between excitation and inhibition in the brain after reprogramming cells. Electrophysiological tests conducted by scientists have demonstrated the ability of new neurons to perceive neurotransmitter signals from other nerve cells, which indicates their successful integration into the local neural network.

In a second experiment on a transgenic mouse model of Alzheimer's disease, the researchers demonstrated that reactive glial cells in the diseased brain of mice can be transformed into functional neurons. Moreover, they showed that even in 14-month-old (which is approximately equivalent to 60 years of human age) animals with simulated Alzheimer's disease, the introduction of the NeuroD1 gene carrier virus into the cerebral cortex ensures the appearance of a large number of new neurons formed as a result of reprogramming of reactive glial cells (in the picture, the nuclei of these neurons glow red).

Subsequent experiments on human glial cell culture have also demonstrated impressive results. Three weeks after the introduction of the NeuroD1 gene into the cells, scientists began to observe their transformation. Under the microscope, it was seen how flat glial cells completely changed their shape, turning into normal-looking neurons with axons and dendrites. Testing the functions of these newly formed neurons confirmed their ability to release neurotransmitters and respond to them.

According to Chen, he and his colleagues dream of transforming the developed cell reprogramming technology into a method of treating the consequences of injuries and diseases of the central nervous system.

Article by Ziyuan Guo et al. In Vivo Direct Reprogramming of Reactive Glial Cells into Functional Neurons after Brain Injury and in an Alzheimer's Disease Model is published in the journal Cell Stem Cell.

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Pennsylvania State University:
Breakthrough could one day help sufferers of brain injury, Alzheimer's disease.

20.12.2013