What Mechanisms Distinguish Astrocytes from Neural Stem Cells?
Neural stem cells produce new neurons in the brain and are critical to memory, learning, and what little capacity for regeneration the brain possesses. Astrocytes are supporting cells that help to maintain the structure and metabolism of brain tissue. Neural stem cells and astrocytes are very similar in lineage and many aspects of their biochemistry. Why are they so functionality different? Given detailed answers to that question, might it be possible to generate more neural stem cells from astrocytes in order to restore lost function in the aging brain with an increased supply of new neurons?
Astrocytes are the most abundant cell type in the mammalian brain and provide structural and metabolic support to neurons, regulate synapses and become reactive after injury and disease. However, a small subset of astrocytes settles in specialized areas of the adult brain where these astrocytes instead actively generate differentiated neuronal and glial progeny and are therefore referred to as neural stem cells. Common parenchymal astrocytes and quiescent neural stem cells share similar transcriptomes despite their very distinct functions. Thus, how stem cell activity is molecularly encoded remains unknown.
Here we examine the transcriptome, chromatin accessibility, and methylome of neural stem cells and their progeny, and of astrocytes from the striatum and cortex in the healthy and ischaemic adult mouse brain. We identify distinct methylation profiles associated with either astrocyte or stem cell function. Stem cell function is mediated by methylation of astrocyte genes and demethylation of stem cell genes that are expressed later. Ischaemic injury to the brain induces gain of stemness in striatal astrocytes. We show that this response involves reprogramming the astrocyte methylome to a stem cell methylome and is absent if the de novo methyltransferase DNMT3A is missing. Overall, targeting DNA methylation to gain stemness or astrocyte features offers a potential therapeutic avenue to repair the diseased nervous system or fight cancer.