Reprogramming fate – how a single protein can trigger brain cell regeneration

A single protein can reverse the developmental clock on adult brain cells, morphing them into stem-like cells that produce neurons and other cell types, a new study investigating brain regeneration finds.

Adult brain cells called astrocytes can be changed into stem-cell like cells that have the ability to become a variety of cell types, including neurons – and all using just one protein, according to a new study by UT Southwestern researchers. Writing in PNAS, the research team concludes that the the findings might someday lead to brain regeneration after disease, injury or degeneration.

Longevity.Technology: During development, mammalian stem cells readily proliferate to produce neurons throughout the brain and cells – called glia – that help support them. Constituting around around 50% of the total cells in the brain, glia play an essential part in regulating brain homeostasis, providing nutritional support to neurons, activating immune response, cleaning up waste, and regulating synaptic transmission and plasticity by insulating nerve fibres.

Research findings “strongly suggest that glia are the first cells changing with aging” [1]; in addition; the mature brain largely loses its stem cell capacity, leaving only two small regenerative zones, or niches, in the adult brain. This loss leaves the brain with extremely limited capacity to heal itself following injury or disease, prompting Chun-Li Zhang, PhD, and his team to investigate a potential solution for brain regeneration.

This loss leaves the brain with extremely limited capacity to heal itself following injury or disease, prompting Chun-Li Zhang, PhD, and his team to investigate a potential solution for brain regeneration.
Chun-Li Zhang, PhD

“We’re showing that it may be possible to reprogram the fate of this subset of brain cells, giving them the potential to rebuild the damaged brain,” said Zhang, study leader and co-corresponding author, who is Professor of Molecular Biology and an Investigator in the Peter O’Donnell Jr Brain Institute [2].

Recent research has suggested that glia can be prompted to produce neurons in some models of brain injury or after genetic manipulation. Although these findings are promising, regenerating healthy brain tissue will require production of multiple cell types, rather than only neurons, said Dr Zhang.

Looking for a way to spur this “multipotent” regeneration, Dr Zhang and his colleagues used a genetic engineering technique in adult mouse brains to induce astrocytes, a subset of glia, to produce different transcription factors, proteins pivotal for controlling cell identity. These experiments showed that a single transcription factor – a protein known as DLX2 – appeared to reprogram astrocytes into neural stem-like cells capable of producing neurons and multiple subtypes of glial cells [3].

The researchers confirmed these findings both using a technique called lineage tracing, in which they followed progeny of the altered astrocytes as they multiplied, as well as marker analysis that showed that these new cells had the expected identities of neurons or glia. Working with the team of co-corresponding author Gary Hon, PhD, Assistant Professor of Obstetrics and Gynecology in the Cecil H and Ida Green Center for Reproductive Biology Sciences and the Lyda Hill Department of Bioinformatics, global gene expression analysis showed that prompting astrocytes to produce DLX2 appeared to reprogram them into stem-like cells with features of both immature brain cells found earlier in development and cells found in the regenerative niches of the adult brain.

Dr Zhang and his colleagues suggest that DLX2 might someday be used as a brain regeneration tool to treat traumatic brain injuries, strokes and degenerative conditions such as Huntington’s disease. Researchers in the Zhang lab are planning to study this approach in animal models.

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