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  • Whereas most studies aiming at reprogramming brain resident

    2018-11-08

    Whereas most studies aiming at reprogramming brain-resident glia into neurons focused on astroglia, NG2 glia represent an interesting alternative cellular source given their abundance and life-long capacity for proliferation (Dimou and Götz, 2014). Here, we found that ∼60% of the induced DCX+ neurons derived from fate-mapped NG2 glia using Sox10-iCreERT2/GFP transgenic mice. GFP-negative-induced neurons could either derive from non-fate-mapped NG2 glia (due to incomplete recombination) or originate from neuronal conversion of other glial cell types. However, we did not obtain evidence for astrocyte conversion into neurons using GLASTCreERT2/GFP mice (Buffo et al., 2008; data not shown), suggesting that reactive astroglia play only a minor role as potential target NCT-501 in this experimental paradigm, consistent with the evidence that only a very small population of reactive astrocytes divide (Bardehle et al., 2013) or acquire stem cell potential after invasive stab wound injury (Buffo et al., 2008; Sirko et al., 2013). Intriguingly, however, Guo et al. (2014) reported conversion of reactive cortical astroglia by forced expression of NeuroD1 using a mouse model with amyloidosis. This suggests that, in the injured brain, several cell populations may be amenable to reprogramming and that precise timing and factors employed may be critical in determining the outcome. Interestingly, NG2 glia exhibit enhanced proliferation in response to injury but remain committed to the oligodendroglial lineage (Dimou et al., 2008). Furthermore, Hughes et al. (2013) showed that these cells are recruited to sites of focal CNS injury. Thus, due to their enhanced proliferation and recruitment following injury, NG2 glia can be readily targeted by retroviruses at the injury site in vivo. Targeting this cell type for reprogramming may have the added benefit that replacement of converted NG2 glia may occur through homeostatic control of NG2 glia density (Hughes et al., 2013) and hence may not result in the exhaustion of the local NG2 glia pool. Retrovirus-mediated expression of NeuroD1 under control of a human NG2 promoter construct was also found to elicit neurogenesis in the cerebral cortex in vivo (Guo et al., 2014), providing independent evidence that NG2 glia can be reprogrammed into induced neurons. Several groups recently reported on transcription-factor-driven fate conversion of local glial cells into induced neuronal cells (Arlotta and Berninger, 2014). Notably, there are major differences to our study with regard to the CNS areas studied, the health status of the tissue in which reprogramming was induced, the cell types targeted, and reprogramming factors used. Most studies employed well-characterized neurogenic transcription factors known to drive neuronal differentiation from neural stem/precursors cells (Buffo et al., 2005), including the proneural genes Ascl1, Neurog2 (Grande et al., 2013; Torper et al., 2013), or NeuroD1 (Guo et al., 2014). Albeit we initially followed the same logic of employing Ascl1, a well-known neuronal reprogramming factor (Berninger et al., 2007; Vierbuchen et al., 2010), forced Ascl1 expression alone failed to induce any appreciable neurogenesis in our lesion paradigm. Our previous work suggested a synergistic enhancement of Ascl1 reprogramming capacity by coexpression of Sox2 (Karow et al., 2012). Whereas we could indeed observe a synergistic effect of these two factors on NG2 glia reprogramming, we were surprised that Sox2 alone was sufficient to trigger de novo emergence of DCX+ cells contrary to the notion that Sox2 prevents neuronal differentiation from neural stem cells. Notably, a similar capacity of Sox2 to convert astrocytes in the adult striatum and spinal cord into DCX+ cells was recently reported (Niu et al., 2013; Su et al., 2014), providing independent evidence for this unexpected capacity of Sox2 to induce a glia-to-neuron fate switch. Interestingly, whereas we do not have direct evidence for continued proliferation, we observed clusters of Sox2-induced DCX+ cells in agreement with Niu et al. (2013). If continued proliferation turns out to be a characteristic feature of Sox2-induced glia NCT-501 reprogramming, this may allow for a local amplification of the pool of induced neurons.