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    • The transient presence of oligodendroblasts

    2018-10-24

    The transient presence of oligodendroblasts could also be explained by their progress into full maturation. Intriguingly, we failed to detect fully mature oligodendrocytes generated by oligodendroblasts. This was determined in three ways: first, by the absence of double EYFP+/MBP+ cells; second, by the lack of accumulation of EYFP+ regadenoson in the CC, as would be expected if post-mitotic cells were constantly generated (a phenomenon we observed with neuroblasts differentiating in olfactory bulb interneurons). These results might be confounded by a gradual switch-off of EYFP expression during cell differentiation; however, we observed that EYFP expression is retained long-term in OB interneurons as well as in oligodendrocytes generated in vitro. In a third approach we also failed to detect EdU-retaining EYFP+ cells in the CC at 12 days post EdU administration. This observation could be due to EdU-induced toxicity on proliferating cells of SEZ origin (Ponti et al., 2013). Although we failed to detect such an effect in the pools of PCNA+, OLIG2+, or SOX2+ cells in the SEZ and the CC at 4 days post EdU (Supplemental Experimental Procedures, Table S2), we cannot exclude the possibility that the small population of oligodendroblasts within the CC might be specifically vulnerable to EdU toxicity, especially since they undergo more rounds of division compared with pOPCs (Figure 4C). Notably, we found that adult NSCs retain their inherent capacity to generate mature, MBP+ oligodendrocytes. This was revealed by co-culturing SEZ-derived neural stem and progenitor cells with dorsal root ganglion neurons, as well as by grafting them in the CC of 21 day old mice, at a time when progenitors of the dorsal SEZ contribute to CC oligodendrogenesis (Tong et al., 2015). Our results are consistent with a recent study in which whole-brain imaging and histological analysis failed to provide any evidence of SEZ-driven remyelination in the cuprizone model (Guglielmetti et al., 2014), but contradict another study in which high levels of remyelination were driven by oligodendroblasts after cuprizone-induced demyelination (Xing et al., 2014). It should be noted that in the latter study, in which demyelination was widespread, the contribution of niche-derived oligodendrogenesis in the area where we induced the focal lesion was low. Xing et al. suggest that sezOPCs might act in a bimodal way, with a first rapid-appearing wave reaching the area of the lesion without fully maturing into oligodendrocytes only to be supplemented by a second myelin-generating wave. Thus, in our model, where demyelination is more restricted and local pOPCs are less affected, we might be observing only the fast-response element of SEZ-driven oligodendrogenesis (see an example of relatively increased representation of oligodendroblasts in the core of the lesion in Figure S2F) because the second wave is not necessary. In the absence of differentiation the alternative fate of oligodendroblasts must be cell death. We failed to detect caspase-3+ (apoptotic) OLIG2+ cells either in the homeostatic or the post injury CC (data not shown), but low numbers of traced cells and fast removal of debris might have been a limiting factor, as apoptotic progenitors can be detected in the cell-dense SEZ (Kazanis et al., 2015). There is a third possibility that SEZ-derived progenitors eventually exit the CC and change their fate, but our labeling strategy would not allow for such a process to be observed. The third major aim of this study was to investigate the relative effects of aging to SEZ-driven and parenchymal oligodendrogenesis. In the aging CC we found a significant decrease in total OLIG2+ cells, but the density of oligodendroblasts remained at young levels even at 25 months. The percentage of proliferating pOPCs was maintained to young-adult levels until 1 year and was significantly reduced in the 2 year CC. Strikingly, no proliferation could be detected in CC oligodendroblasts, although their fast-response properties after demyelination remained similar to that observed in the young CC; thus, their numbers were probably maintained by the switch toward oligodendrogenesis that we observed in the aging SEZ. In the 14 month old mice demyelinated CC, oligodendroblast numbers were boosted by a dramatic increase in both their proliferation locally, and in their generation in the SEZ. In the 25 month mouse brain, the proliferative capacity of the SEZ was reduced but the trend toward oligodendrogenesis remained, as has been recently demonstrated (Capilla-Gonzalez et al., 2013). Moreover, the levels of EYFP expression remained unchanged despite the reduction in cell density (Supplemental Experimental Procedures), and mitotic response in the CC was increased after demyelination.