Adult brain can replace key cells lost in NMOSD, study finds
Scientists identify astrocyte repair mechanism in brains of people, mice
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Researchers have identified a mechanism by which the adult brain can replace astrocytes, the neuron-supporting cells in the brain that are attacked and lost in people with neuromyelitis optica spectrum disorder (NMOSD).
Using mice with NMOSD-like disease, the researchers found that surviving astrocytes around lesions will replicate their DNA as if they’re going to divide, but then, instead of dividing right away, the cells enter an intermediate stage where they stretch and transport the newly generated DNA into regions of damage. Signs of a similar process were identified in brain samples from people with NMOSD.
“The findings of our study reveal a previously unknown ability of the adult brain to repair itself,” Bruno Weber, PhD, the study’s senior author and director of the Institute of Pharmacology and Toxicology at the University of Zurich, said in a university news story. “They point toward new ways of supporting recovery from ailments involving the loss of astrocytes.”
The researchers also identified specific genes and signaling pathways temporarily activated during this process that have the potential to be relevant targets for pharmacological interventions to accelerate brain repair.
The findings were described in the study, “Focal astrocyte loss reveals nuclear translocation during lesion repopulation,” published in Nature Neuroscience.
Autoimmune attacks and astrocytes
NMOSD is caused in most cases by the production of self-targeting antibodies that attack aquaporin-4 (AQP4), a protein highly present in astrocytes, the star-shaped brain cells that play vital roles supporting the activities of nerve cells, or neurons.
These autoimmune attacks cause astrocytes to die, which drives inflammation and eventual neuronal damage and death.
Although astrocyte death plays a key role in NMOSD and many other neurological disorders, scientists haven’t had a detailed understanding of exactly how the brain responds to the death of these cells.
Weber and colleagues wanted to answer an important question: When astrocytes in one part of the brain die, what happens to the surviving astrocytes in neighboring brain regions?
It had long been assumed that when astrocytes are lost due to injury or autoimmune diseases such as NMOSD, the adult brain cannot fully replace them. The researchers found that this is not true.
Using advanced imaging techniques and a mouse model where localized astrocyte death is driven by anti-AQP4 antibodies — similar to what happens in NMOSD — the team focused on the activity of surviving astrocytes next to regions of damage in the outer folds of the brain.
They found that after astrocyte injury, surviving astrocytes begin replicating to replace lost astrocytes — but they do so in an unconventional way.
When a cell divides, it dismantles its nucleus (where all DNA is stored) and makes a copy of its DNA to form two nuclei, one around the original DNA and the other around the copied DNA. The rest of the cell then splits, forming two new cells, each with its own nucleus. The newly formed cells can then move where they are needed.
The team found that astrocytes replicate their DNA and form two new nuclei following normal patterns. But instead of splitting off right away into two cells that each go their separate ways, the astrocyte changes its shape, essentially squishing one of the new nuclei towards the area of damage without actually dividing to form two new cells.
These findings suggest that astrocytes surrounding lesions replicate their DNA, but “remain in a multinucleated intermediate phase, squeezing and guiding [newly formed] nuclei to new astrocytic territories” to restore the astrocyte network, the researchers wrote.
While the team found that the astrocytes eventually split into two independent cells, their approach did not allow them to determine the precise timing of this split.
This process contrasts with how astrocytes grow in the developing brain, where two entirely new cells are immediately created, the researchers noted.
Additional analysis showed that astrocytes surrounding damaged astrocytes temporarily activate an injury-associated gene signature. The researchers identified several changes in gene activity and signaling pathways associated with astrocyte generation, regenerative activity, and remodeling that attenuated as new astrocytes repopulated lesion sites.
These newly identified gene activity changes “could serve as starting points in the future for influencing post-disease and -injury regeneration processes,” Weber said.
When analyzing brain tissue samples from people with NMOSD, the team found that, surrounding lesions, a fraction of surviving astrocytes had abnormal shapes and more than one nucleus — consistent with the atypical replication patterns seen in the mouse model.
“Our data suggest that astrocyte remodeling responses involving [multiple nucleus] may also occur in human [diseases that affect astrocytes],” the researchers wrote. “However, the functional consequences of these cellular states in NMOSD or other neurological diseases remain unknown.”
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