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Stem cell research

A winning formula

München, 03/04/2016

In the adult brain, nerve cells lost due to acute injury or chronic damage generally cannot be replaced. Now Munich researchers have successfully converted glia cells into neurons, using a surprisingly simple and highly efficient method.

Neurons generated by direct reprogramming. Source: Götz Group

Most of the nerve cells in the human brain are formed in early life, and in adults the capacity for neurogenesis is restricted to a few areas of the forebrain. Consequently, in the event of traumatic injury, the adult brain is generally unable to replace the neurons that have been lost. For the past several years, Professor Magdalena Götz, Head of the Institute for Physiological Genomics in LMU‘s Biomedical Center and Director of the Institute for Stem Cell Research at the Helmholtz Center Munich, has been exploring ways to persuade glia cells, which serve as a structural scaffold for nerve cells in the brain, to transdifferentiate into neurons. In 2005, she reported the conversion of a small fraction of glia cells activated by brain damage into nerve-cell precursors in vivo. However, most of these neural progenitor cells died within a few weeks. With the help of a novel method, Götz and her team have now succeeded in inducing virtually all the treated glia cells to become nerve cells. Furthermore, these neurons survived for many weeks. In this latest study, the Munich researchers introduced into the glia cells a specific protein factor which stimulated their transformation into neurons, and a second agent that protects the transdifferentiating cells against oxidative stress. Their findings have now been published in the leading journal “Cell Stem Cell”.

When Götz’s group used cell cultures to study the transformation of glia into neural progenitors in more detail, they discovered that very many of the cells died during the process. In collaboration with Dr. Marcus Conrad (Helmholtz Zentrum Munich and German Center for Neurodegenerative Diseases, DZNE) and his colleagues, they then found – to their surprise – that the neurons, but not the glia cells, were undergoing a very particular form of apoptosis (programmed cell death) called ferroptosis, which is triggered by the accumulation of chemically reactive oxygen species. It turns out that when glia cells are in the process of switching their metabolism into the nerve-cell mode, they are exposed to oxidative stress. Under these conditions, they are also ill-equipped to cope with such stress, because they cannot yet activate the protective mechanisms that neutralize the aggressive oxidizing agents.

Survival is the key

And indeed, when the lessons learned from these cell-culture studies were applied in vivo, the effects were dramatic. When glia cells located near sites of traumatic brain injury were forced to express the gene for the factor that promotes formation of nerve cells, about 10% of them gave rise to neurons. However, if they were also induced to produce the protein Bcl-2, an inhibitor of apoptosis, the conversion rate rose to around 80%. Further addition of vitamin E, an antioxidant, resulted in the transformation of almost all glia cells into essentially fully mature nerve cells. “These results revolutionize the whole approach of turning glia cells at sites of brain damage into neurons that can compensate for those lost to injury,” says Sergio Gascón, first author of the new study.

Conventional strategies for the development of new therapies for the treatment of brain damage, due to stroke or dementia, concentrate on finding ways to replace the dead nerve cells. However, very few areas in the adult human brain contain the neuronal stem cells qualified to do so. “But our approach, which uses glia cells as a source of new nerve cells, makes it possible to repair damage in brain regions that are remote from a stem-cell niche,” Magdalena Götz points out. “For the first time, we have now been able to generate not only very many, but also fully mature, nerve cells using this strategy. We can now study how these new nerve cells form connections with their older neighbors – and determine whether they are properly integrated into the existing nerve-cell network.”
(Cell Stem Cell)     LMU/Helmholtz-Zentrum München