Previous studies have found similarities in gene expression between resting brain stem cells and normal astrocytes even though they have very different functions. New research into epigenetic changes in astrocytes from scientists at the German Cancer Research Center (DFKZ) and Heidelberg University helps explain how this is possible. Details of the work are published in a Nature paper titled, “DNA methylation controls stemness of astrocytes in health and ischaemia.”
Most astrocytes support nerve cells in the brain. Brain stem cells are a special type of astrocyte that can differentiate into various kinds of brain cells. Using experiments in mice, the researchers showed that a lack of blood supply in the brain epigenetically reprograms astrocytes into brain stem cells, which can then give rise to nerve progenitor cells. The findings have implications for regenerative medicine. They suggest that astrocytes could potentially be reprogrammed to replace damaged nerve cells.
In the paper, the researchers explained how they studied the link between the two nerve cell types. They isolated ordinary astrocytes and brain stem cells from the ventricular-subventricular zone (vSVZ), a region of adult mice brains with young neurons. They analyzed gene expression data as well as patterns of methylation in the cells. They noticed that brain stem cells have a unique methylation pattern that sets them apart from other astrocytes.
Specifically, “certain genes are demethylated in brain stem cells that are otherwise only used by nerve precursor cells. This allows the brain stem cells to activate these genes in order to produce nerve cells themselves,” explained Lukas Kremer, a doctoral student at DFKZ and first author of the current publication. Normal astrocytes have the genes in this pathway blocked by DNA methylation.
Next, the researchers explored whether methylation could be used to convert astrocytes into brain stem cells in regions of the brain outside of the vSVZ. If it was possible, it would be “an important step for regenerative medicine to repair damaged areas of the brain,” noted Ana Martin-Villalba, PhD, a group leader at DKFZ and one of the lead researchers on the study. “Techniques to specifically alter the methylation profile could represent a new therapeutic approach to generate new neurons and treat nerve diseases.”
The team knew from prior studies exploring conditions like stroke or brain injuries that when the blood supply to the brain is cut off, the number of new nerve cells increases. To investigate whether altered methylation was involved in the process, they cut off the blood supply to the mice’s brains for a short time. They found that astrocytes with the typical stem cell methylation profile were present even outside the vSVZ as well as more nerve progenitor cells.
“The lack of blood supply apparently causes astrocytes in certain areas of the brain to redistribute the methyl marks on their DNA in such a way that their stem cell program becomes accessible. The reprogrammed cells then begin to divide and form precursors for new neurons,” said Simon Anders, PhD, project group leader at Heidelberg and one of the lead researchers on the study. ”If we understand these processes better, we may be able to specifically stimulate the formation of new neurons in the future. For example, after a stroke, we could strengthen the brain’s self-healing powers, so that the damage can be repaired.”
