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Researchers from the German Cancer Research Center (DKFZ) and Heidelberg University have discovered a method by which brain stem cells—often indistinguishable from typical astrocytes—can be epigenetically reprogrammed to produce nerve progenitor cells. Their findings, published in Nature, reveal how alterations in DNA methylation enable astrocytes to adopt stem cell-like properties, a discovery that could have potential applications in regenerative medicine.
Understanding Astrocyte Functionality
Astrocytes, the most common glial cells in the brain, are traditionally seen as support cells. They regulate synapses, provide neurons with nutrients, form parts of the blood-brain barrier, and assist immune responses. However, some astrocytes possess the unique ability to produce neurons and other brain cells, functioning as brain stem cells. The challenge for scientists has been understanding how brain stem cells, which closely resemble ordinary astrocytes, perform such dramatically different functions.
Ana Martin-Villalba, a stem cell researcher at DKFZ, explained the key to this puzzle: “How they can perform such different functions and what makes up the stem cell properties was previously completely unclear.” The team’s study reveals that the answer lies in the methylation patterns of these cells.
DNA Methylation: Unlocking Stem Cell Potential
In their research, the teams led by Martin-Villalba and Simon Anders at Heidelberg University isolated astrocytes and brain stem cells from the ventricular-subventricular zone (vSVZ) of adult mice brains. Using mRNA sequencing, they analyzed gene expression at the single-cell level, while also mapping the entire genome's methylation patterns—often referred to as the methylome.
Methylation involves adding chemical markers to DNA, which effectively turns off sections of the genetic code that are not needed by the cell. This process is critical for determining a cell's identity. Through their analysis, the researchers observed that brain stem cells display a distinct methylation profile that sets them apart from regular astrocytes.
“Unlike normal astrocytes, certain genes are demethylated in brain stem cells that are otherwise only used by nerve precursor cells,” said Lukas Kremer, the study's lead author. "This allows the brain stem cells to activate these genes in order to produce nerve cells themselves.” Co-author Santiago Cerrizuela further elaborated: “This pathway is denied to ordinary astrocytes, as the required genes are blocked by DNA methylation.”
Impact of Blood Supply on Reprogramming
A crucial question for the team was whether it would be possible to induce astrocytes outside the vSVZ to adopt stem cell-like characteristics. This question is particularly significant for regenerative medicine, which seeks ways to repair damaged brain tissue. Previous research had indicated that brain injuries or strokes, which reduce blood supply to affected areas, lead to increased nerve cell production. The researchers hypothesized that altered methylation profiles might be involved in this process.
To test this, they briefly interrupted the blood supply to the brains of mice, mimicking conditions of stroke. The result was striking: astrocytes in areas beyond the vSVZ began displaying the stem cell methylation profile, and the number of nerve progenitor cells in those regions increased.
Martin-Villalba explained, “Our theory is that normal astrocytes in the healthy brain do not form nerve cells because their methylation pattern prevents them from doing so. Techniques to specifically alter the methylation profile could represent a new therapeutic approach to generate new neurons and treat nerve diseases.”
Simon Anders added, “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”.
Publication Details
Kremer, L.P.M., Braun, M.M., Ovchinnikova, S. et al. Analyzing single-cell bisulfite sequencing data with MethSCAn. Nat Methods (2024). https://doi.org/10.1038/s41592-024-02347-x
Understanding Astrocyte Functionality
Astrocytes, the most common glial cells in the brain, are traditionally seen as support cells. They regulate synapses, provide neurons with nutrients, form parts of the blood-brain barrier, and assist immune responses. However, some astrocytes possess the unique ability to produce neurons and other brain cells, functioning as brain stem cells. The challenge for scientists has been understanding how brain stem cells, which closely resemble ordinary astrocytes, perform such dramatically different functions.
Ana Martin-Villalba, a stem cell researcher at DKFZ, explained the key to this puzzle: “How they can perform such different functions and what makes up the stem cell properties was previously completely unclear.” The team’s study reveals that the answer lies in the methylation patterns of these cells.
DNA Methylation: Unlocking Stem Cell Potential
In their research, the teams led by Martin-Villalba and Simon Anders at Heidelberg University isolated astrocytes and brain stem cells from the ventricular-subventricular zone (vSVZ) of adult mice brains. Using mRNA sequencing, they analyzed gene expression at the single-cell level, while also mapping the entire genome's methylation patterns—often referred to as the methylome.
Methylation involves adding chemical markers to DNA, which effectively turns off sections of the genetic code that are not needed by the cell. This process is critical for determining a cell's identity. Through their analysis, the researchers observed that brain stem cells display a distinct methylation profile that sets them apart from regular astrocytes.
“Unlike normal astrocytes, certain genes are demethylated in brain stem cells that are otherwise only used by nerve precursor cells,” said Lukas Kremer, the study's lead author. "This allows the brain stem cells to activate these genes in order to produce nerve cells themselves.” Co-author Santiago Cerrizuela further elaborated: “This pathway is denied to ordinary astrocytes, as the required genes are blocked by DNA methylation.”
Impact of Blood Supply on Reprogramming
A crucial question for the team was whether it would be possible to induce astrocytes outside the vSVZ to adopt stem cell-like characteristics. This question is particularly significant for regenerative medicine, which seeks ways to repair damaged brain tissue. Previous research had indicated that brain injuries or strokes, which reduce blood supply to affected areas, lead to increased nerve cell production. The researchers hypothesized that altered methylation profiles might be involved in this process.
To test this, they briefly interrupted the blood supply to the brains of mice, mimicking conditions of stroke. The result was striking: astrocytes in areas beyond the vSVZ began displaying the stem cell methylation profile, and the number of nerve progenitor cells in those regions increased.
Martin-Villalba explained, “Our theory is that normal astrocytes in the healthy brain do not form nerve cells because their methylation pattern prevents them from doing so. Techniques to specifically alter the methylation profile could represent a new therapeutic approach to generate new neurons and treat nerve diseases.”
Simon Anders added, “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”.
Publication Details
Kremer, L.P.M., Braun, M.M., Ovchinnikova, S. et al. Analyzing single-cell bisulfite sequencing data with MethSCAn. Nat Methods (2024). https://doi.org/10.1038/s41592-024-02347-x