Laboratory mice to change the identity of a brain cell

It is now possible in laboratory mice to change the identity of a brain cell to a neuron by introducing genes into it with inactive viruses. This "cellular reprogramming" process represents a promising way to repair the brain, which will still require a lot of work, but which already appears transposable to humans.

Most neurological diseases are accompanied by neuron losses that can be very specific to a particular region or neural type. For several years, many studies have tried to replace these missing neurons with grafted neurons, hoping that they could be integrated into the damaged circuits and thus restore the defective functions. The first attempts were made using embryonic cells, which were more or less effective and highly controversial in ethical terms.

Laboratory mice to change the identity of a brain cell

method for reprogramming glial cells into glutamatergic or GABAergic neurons

Very recently, the team of Magdalena Goetz and Benedikt Berninger in Munich, and in particular the work of Christophe Heinrich (currently CNRS researcher at the Grenoble Institute of Neurosciences) have shown that it is possible to reprogram glial cells to generate new neurons. By introducing, using inactive viruses, differentiation genes capable of reprogramming these cells, researchers can change their identity. (1,2). Very encouragingly, human brain cells, isolated in vitro from surgical resection parts from patients, have also been reprogrammed into induced neurons (3).

Glutamatergic neuron induced (in red) from a glial cell, provided with recapture proteins (in green)

Glial cells are generally abundant in the regions affected by the disease, and proliferate in most brain diseases associated with neuronal deaths (Parkinson's disease, Alzheimer's disease, certain forms of epilepsy, etc...). It even seems that they contribute to the emergence of symptoms of some of these diseases. Their reprogramming into neurons "in vivo" makes it possible to consider new therapeutic solutions that would avoid transplanting cells. In addition, depending on the genes that are introduced into resident glial cells, excitatory neurons (which synthesize glutamate) or inhibitors (which synthesize GABA (link)) can be generated (4). The first results show that these new neurons integrate rather well into their environment (they are already there!) (5).

Following this pioneering work in the field, many European and American laboratories are currently studying the mechanisms underlying this glie-neuron cell reprogramming. It remains to be seen whether these "induced" neurons are capable of correcting neurological disorders resulting from the loss of their predecessors...

To answer this question, Christophe Heinrich's group is studying in Grenoble the possibility that these neurons derived from glial cells can thwart the development of Epilepsy attacks in a sick brain. It has obtained financial support from the National Research Agency (ANR) and the French Foundation for Epilepsy Research.

>>> Notes

Many thanks to Christophe Heinrich for his help in writing this article!

Heinrich, C., Spagnoli, F.M., Berninger, B., 2015. In vivo reprogramming for tissue repair. Nature Cell Biology 17, 204-211.
Heinrich C, Gascon S, Masserdotti G, Lepier A, Sanchez R, Simon-Ebert T, Schroeder T, Götz M and Berninger B. Generation of subtype-specific neurons from postnatal astroglia of the mouse cerebral cortex. Nature Protocols, 2011, 6 (2): 214-228.
Karow M, Sánchez R, Schichor C, Masserdotti G, Ortega F, Heinrich C, Gascón S, Khan MA, Lie DC, Dellavalle A, Cossu G, Goldbrunner R, Götz M and Berninger B. Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells.
Cell Stem Cell, 2012, 11 (4): 471-6
Heinrich C, Blum R, Gascon S, Masserdotti G, Tripathi P, Sanchez R, Tiedt S, Schroeder T, Götz M and Berninger B. Directing astroglia from the cerebral cortex into subtype specific functional neurons.
PLoS Biology, 2010, 8 (5): e1000373.
Heinrich C, Bergami M, Gascón S, Lepier A, Viganò F, Dimou L, Sutor B, Berninger B and Götz M. Sox2- mediated conversion of NG2 glia into induced neurons in the injured adult cerebral cortex. Stem Cell Reports, 2014, 3 (6): 1000-14