The authors of today's research report on success in use of a gene therapy to convert glial cells into neurons in a living mouse brain, and thereby improve the normally limited recovery that takes place following brain injury, such as that caused by a stroke. A number of research groups are investigating this class of approach to enhance regeneration in the brain, an organ that has little capacity to repair itself. The capacity that does exist is generated by neural stem cells that, arguably, continue to produce new neurons at some pace throughout life. As for all stem cell populations, activity declines with age, however. An increased supply of new neurons, provided that they are capable of correctly maturing and integrating into neural circuits, should prove beneficial.
Interestingly, increasing the supply of neurons is not just relevant to regeneration in the brain. Functions such as memory rely on changes in neural networks, and in turn on a supply of new neurons. It is possible that increasing the pace at which new neurons emerge could improve cognitive function even in younger people. We are a long way removed from that sort of application of new biotechnology, however - the focus today is very much on addressing age-related conditions.
Researchers have pioneered a new approach to regenerate functional neurons using glial cells, a group of cells surrounding every single neuron in the brain that provide essential support to neurons. Unlike neurons, glial cells can divide and regenerate themselves, especially after brain injury. Researchers previously reported that a single genetic neural factor, NeuroD1, could directly convert glial cells into functional neurons inside mouse brains with Alzheimer's disease, but the total number of neurons generated was limited. The research team believed that this limited regeneration was due to the retroviral system used to deliver NeuroD1 to the brain. In the current study, the research team used the AAV viral system, which is now the first choice for gene therapy in the nervous system, to deliver NeuroD1 into mouse motor cortex that had suffered from stroke.
Many neurons die after stroke but surviving glial cells can proliferate and form a glial scar in the stroke areas. The AAV system was designed to express NeuroD1 preferentially in the glial cells that form these scars, turning them directly into neuronal cells. Such direct glia-to-neuron conversion technology not only increased neuronal density in the stroke areas, but also significantly reduced brain tissue loss caused by the stroke.
"The most exciting finding of this study is to see the newly converted neurons being fully functional in firing repetitive action potentials and forming synaptic networks with other preexisting neurons. They also send out long-range axonal projections to the right targets and facilitate motor functional recovery. "Because glial cells are everywhere in the brain and can divide to regenerate themselves, our study provides the proof-of-concept that glial cells in the brain can be tapped as a fountain of youth to regenerate functional new neurons for brain repair not only for stroke but also for many other neurological disorders that result in neuronal loss."
Adult mammalian brains have largely lost neuroregeneration capability except for a few niches. Previous studies have converted glial cells into neurons, but the total number of neurons generated is limited and the therapeutic potential is unclear. Here, we demonstrate that NeuroD1-mediated in situ astrocyte-to-neuron conversion can regenerate a large number of functional new neurons after ischemic injury. Specifically, using NeuroD1 AAV-based gene therapy, we were able to regenerate one third of the total lost neurons caused by ischemic injury and simultaneously protect another one third of injured neurons, leading to a significant neuronal recovery. RNA-sequencing and immunostaining confirmed neuronal recovery after cell conversion at both the mRNA level and protein level.
Brain slice recordings found that the astrocyte-converted neurons showed robust action potentials and synaptic responses at 2 months after NeuroD1 expression. Tracing revealed long-range axonal projections from astrocyte-converted neurons to their target regions in a time-dependent manner. Behavioral analyses showed a significant improvement of both motor and cognitive functions after cell conversion. Together, these results demonstrate that in vivo cell conversion technology through NeuroD1-based gene therapy can regenerate a large number of functional new neurons to restore lost neuronal functions after injury.