Researchers reveal how DNA methylation can reprogram astrocytes into neural stem cells
A recent study has demonstrated that astrocytes can be reprogrammed into neural stem cells, offering new therapeutic prospects for neural diseases such as stroke.
In a collaborative study, researchers from the German Cancer Research Center (DKFZ) and Heidelberg University (both Heidelberg, Germany) have revealed how epigenetic changes can trigger the reprogramming of astrocytes into neural stem cells by altering their methylation profiles. By analyzing gene expression and epigenetic patterns in an animal model, the study provided insights into the molecular mechanisms of astrocyte reprogramming, highlighting a promising target for neural repair and stroke treatment.
Astrocytes, a type of glial cell, are essential for supporting neurons and regulating brain functions. A small subset of astrocytes act as ‘neural stem cells’ in specific brain regions and has the capacity to generate neurons and other brain cells. Despite the genetic similarity between neural stem cells and regular astrocytes, our understanding of their differing functions has been unclear.
To demystify this topic the team conducted several experiments. First, they isolated astrocytes and neural stem cells from the ventricular-subventricular zone (vSVZ) in adult mice. Using single-cell bisulfite sequencing, they analyzed gene expression, chromatin accessibility and DNA methylation patterns across individual cells from different brain regions, under both healthy and restricted blood flow conditions.
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Their findings revealed distinct methylation patterns linked to astrocyte function and neural stem cell activity. Interestingly, neural stem cells exhibited a unique DNA methylation profile that set them apart from regular astrocytes. Specifically, certain genes that are active in nerve precursor cells were demethylated in neural stem cells, enabling them to produce nerve cells. In contrast, these genes were silenced by DNA methylation in regular astrocytes. Neural stem cells in the vSVZ expressed stem cell markers such as TLX and TROY, which were absent in regular astrocytes, further indicating that specific methylation patterns regulate their stem cell-like properties.
Next, the researchers further investigated whether the methylation patterns observed in neural stem cells could support stem cell activity in other brain regions beyond the vSVZ. Given that recent studies have indicated that restricted blood flow due to brain injury can induce new nerve cell generation, they investigated whether changes in methylation profiles contribute to nerve cell regeneration.
To do this, the team briefly interrupted the blood supply to the mice’s brain and observed that astrocytes with a stem cell-like methylation profile appeared outside the vSVZ, along with an increased number of nerve progenitor cells. Simon Anders (Heidelberg University), who co-led the study, explained that, “the lack of blood flow 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.”
These observations highlight the crucial role of DNA methylation in gene expression and cellular function, influencing whether cells act as regular astrocytes or neural stem cells. The researchers hope that further exploration into altering the methylation patterns of regular astrocytes could enable these cells to generate new neurons, potentially leading to new therapeutic approaches to treat nerve diseases.
“If we understand these processes better, we may be able to specifically stimulate the formation of new neurons in the future,” continued Anders. “For example, after a stroke, we could strengthen the brain’s self-healing powers, which normally just don’t seem to be sufficiently active, so that the damage can be repaired.”
