Reprogramming adult differentiated cells into lineage-restricted precursor cells or pluripotent stem cells could provide a cellular population from which to derive new neurons and hence promote regeneration in cases of brain injury or disease. Although such reprogramming has been achieved in vitro, it has not been demonstrated in vivo. Now, Zhang and colleagues show that resident astrocytes in the adult mouse brain can be reprogrammed to generate neuroblasts and that these neuroblasts can form functional neurons.
To examine whether astrocytes can be reprogrammed in vivo, the authors first generated various lentiviruses that each included a transcription factor or microRNA gene downstream of the promoter for glial fibrillary acid protein (GFAP), an astrocytic marker. They then injected combinations of these viruses into the striatum of adult mice.
After 4 weeks, the authors detected cells that morphologically resembled neuroblasts
After 4 weeks, the authors detected cells that morphologically resembled neuroblasts in mice that had been infected with lentiviruses that collectively expressed four transcription factors, including SOX2. These cells expressed doublecortin (DCX), a marker of neuroblasts and immature neurons, and showed labelling with bromodeoxyuridine (BrdU), indicating that they were newly produced. Interestingly, removal of the SOX2-expressing lentivirus from the virus pool prevented the emergence of such cells, whereas infection with this virus only could induce DCX-positive cells.
These results suggest that SOX2 expression alone can reprogramme astrocytes in vivo to form neuroblasts, which the authors termed 'induced adult neuroblasts' (iANBs). To show that iANBs were derived from astrocytes, transgenic mice in which astrocytes expressed yellow fluorescent protein (YFP) were infected with the SOX2 lentivirus. After 5 weeks, DCX-positive cells in the striatum all showed YFP expression, confirming that iANBs have an astrocytic origin.
Can iANBs form functional neurons? Nine weeks after infection, few iANBs expressed the neuronal marker NeuN, so the authors generated a lentivirus containing the genes for brain-derived neurotrophic factor and noggin — which promote the survival and maturation of neurons generated in the subventricular zone of the lateral ventricle — downstream of the GFAP promoter. Co-injection of this virus and the SOX2 lentivirus into the striatum of adult mice led to the appearance of cells expressing BrdU and NeuN, indicating that neurons had been generated from iANBs. Electrophysiological recordings in striatal slices revealed that these cells exhibited spontaneous synaptic currents, indicating that they had functionally integrated into local neuronal networks.
This proof-of-principle study shows that functional neurons can be formed from reprogrammed astrocytes in vivo, a finding that could have important implications for future neuroregeneration research.
Niu, W. et al. In vivo reprogramming of astrocytes to neuroblasts in the adult brain. Nature Cell Biol. http://dx.doi.org/10.1038/ncb2843 (2013)
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Yates, D. Reprogramming the residents. Nat Rev Neurosci 14, 739 (2013). https://doi.org/10.1038/nrn3620