Niche derived oligodendrocyte progenitors: a source of rejuvenation or complementation for local oligodendrogenesis?

With the recent revelations that strikingly plastic cytogenic and migratory processes take place in the adult mammalian brain, it cannot anymore be considered as an organ static or utterly unequipped against injury. The Subependymal zone (SEZ) or otherwise called with its embryonic equivalent as the Subventricular zone (SVZ), is one major cytogenic area located at the lateral wall of the lateral ventricles (Luskin, 1993) and is known to continuously contribute new cells to different brain areas both during homeostasis and following injury (Kazanis, 2009). A well-documented role of the SEZ in rodents is the constant supplementation of neural progenitors to the olfactory bulb (OB), through the rostral migratory stream (Lois and Alvarez-Buylla, 1994). Once in the OB, SEZ-derived neural progenitors differentiate into GABAergic (mainly) and glutamatergic neurons, depending on their exact anatomical origin in the niche (Brill et al., 2009). Cellular integration and survival depends on sensory olfactory inputs (i.e. exposure to new odours), as well as on the ability of these neural progenitors to form the appropriate synaptic connections with other cells (Mouret et al., 2008). This supply of new neurons to the OB is not only necessary for olfactory learning and memory but also for successful social and mating encounters in rodents (Oboti et al., 2011). Despite its initially identified neurogenic output, the SEZ is now known to also generate oligodendrocyte progenitor cells (OPCs) from Olig2-expressing transit-amplifying progenitors in the niche (TaPs/ also known as type C cells) . In the adult murine brain these SEZ-derived OPCs can successfully migrate to the closely located corpus callosum (Cayre et al., 2006; Menn et al., 2006) (Figure 1). However, very little is known about the characteristics of niche-derived OPCs and the functions they might serve. In contrast to the less studied SEZ-derived OPCs, much more is known about parenchymal OPCs. During development they are generated in different waves (Kessaris et al., 2006), firstly from sonic hedgehog (shh)-responsive ventral progenitors and at later stages from dorsal progenitors in a shh-independent manner (Fogatry et al., 2005). Subsequently, OPCs migrate away to populate the grey and white matter and to give rise to the myelinating cells of the central nervous system, the oligodendrocytes. Once, early post-natal myelination program is concluded, some OPCs remain to give rise to the parenchymal adult OPCs which are equally distributed around the brain and account for a striking 5% of the total cell populations with the majority of them (>80%) being mitotically active (Polito and Reynolds, 2005; Young et al., 2013). These OPCs are capable of responding to demyelinating insults by quickly migrating to the injured site where they proliferate and give rise to new myelinating oligodendrocytes (Franklin and ffrench-Constant, 2008). In light of the abundance of adult parenchymal OPCs and their capacity to successfully replace damaged oligodendrocytes following injury, the role of SEZ-derived OPCs in the adult brain remains a puzzle. One way to address this puzzle is to look into the development of adult OPCs. Experiments performed in the late 80's suggested that adult OPCs originate from a fraction of the late-embryonic and perinatal OPC population that escapes terminal differentiation to oligodendrocytes (Wren et al., 1992). Over time, these perinatal OPCs switch to a significantly different adult-like behaviour with an almost 4-fold slower cell cycle as compared to perinatal OPCs (Shi et al., 1998; Tang et al., 2000; Young et al., 2013). Moreover, adult and perinatal OPCs respond differently to growth factors such as platelet derived growth factor (PDGF) and neuregulin in vitro (Shi et al., 1998); downregulate membrane ion channel expression (Clarke et al., 2012); and have different migratory and remyelinating properties (Windrem et al., 2004). With ageing, increasing numbers of adult OPCs start expressing various markers of senescence (Kujuro et al., 2010) and their efficiency in regenerating damaged oligodendrocytes significantly deteriorates. Therefore, one possible scenario is that, the main function of SEZ-derived OPCs is to replenish the ageing pool of adult parenchymal OPCs, with freshly-born progenitors from adult neural stem cells. This “rejuvenating hypothesis”, according to which a convergence between niche and parenchymal OPCs exists, leads to a clear prediction, that the adult OPC pool in the supra-ventricular corpus callosum should gradually get dominated by self-renewing OPCs of SEZ origin. Recently, it was suggested that low-level oligodendrocyte turnover occurs in the corpus callosum (Young et al., 2013); therefore, the numbers of oligodendrocytes generated by SEZ-derived progenitors should also increase over time, with the contribution of SEZ-driven oligodendrogenesis becoming more apparent in cases of remyelination (Figure 1). An alternative scenario regarding the fate of SEZ-derived OPCs could be drawn by looking at the neurogenic output of the SEZ. Progenitors of neuronal commitment (neuroblasts) are generated within the niche by stationary adult neural stem cells and TaPs. Subsequently, they migrate in chains to the olfactory bulb where they disperse radially to the different neuronal layers (Lois and Alvarez-Buylla, 1994; Brill et al., 2009), where a small fraction survives long-term, by fully differentiating and integrating into existing networks, whilst the rest die. There is no evidence for long-term self-renewal potential of neuroblasts and the levels of SEZ-driven neurogenesis at the OB are controlled by the proliferative activity of stem cells into the distant niche, as well as by the rate of migration and differentiation/integration of the neuroblasts. Notably, cellular integration and survival of SEZ-derived neuroblasts depends on sensory olfactory activity. Long-term exposure to odor enriched environments or to odor discrimination learning protocols, dramatically increases the survival of SEZ-derived neuroblasts in the murine OB (Mouret et al., 2008; Oboti et al., 2011). This activity-dependent neurogenesis is also prominent in the other major stem cell niche of the adult brain, the subgranular zone (SGZ) of the dentate gyrus (DG). New neurons are born in the SGZ before migrating and populating the inner granule cell layer of the DG as mature glutamatergic granule cells. It has been documented that various environmental cues ranging from voluntary exercise to environmental enrichment and training on associative tasks, significantly increase adult DG neurogenesis (Ma et al., 2009). If this scenario also applies to SEZ-driven oligodendrogenesis, then niche-derived OPCs enter the corpus callosum and either differentiate to mature oligodendrocytes or die, depending on local demands. According to this “complementarity hypothesis”, in which niche and parenchymal oligodendrogeneses co-exist but operate independently, the prediction would be i) a lack of SEZ-derived OPC accumulation within the pool of OPCs in the corpus callosum, and ii) a gradual increase in numbers of SEZ-generated oligodendrocytes due to the suggested low-level oligodendrocyte turnover that would be dramatically accelerated in cases of remyelination (Figure 1). In support of this scenario in experimentally-induced corpus callosum demyelination neuroblasts are capable of escaping their route to the OB and migrate towards the lesion where they establish synaptic contacts with axons (Etxeberria et al., 2010) identical to parenchymal OPCs during development (Karadottir et al., 2005; Kukley et al., 2007; Ziskin et al., 2007) . Subsequently they differentiate into myelinating oligodendrocytes with chordin and netrin1 having been identified asregulatory signals in this process (Jablonska et al., 2010; Cayre et al. 2013). This response-mediated oligodendrogenic plasticity of the SEZ has also been documented in animal models of experimental autoimmune encephalitis with increased oligodendrogenesis from the niche in the expense of neurogenic fates (Tepavcevic et al., 2011). But if this is how SEZ-derived oligodendrogenesis occurs, does it actually present any advantages over the parenchymal oligodendrogensis? As old age seems to be the major factor underlying the decreased efficiency of remyelination in the CNS (Hampton et al., 2012; Ruckh et al., 2012; Sim et al., 2002), the existence of an active neural stem cell population that can either constantly supply new-born OPCs (rejuvenating hypothesis), or can directly generate high numbers of oligodendrocytes upon demand (complementary hypothesis), provides a valuable explanation for SEZ-driven oligodendrogenic potential. Notably, neural stem cells located in the SEZ retain their differentiation potential during ageing (Ahlenius et al., 2009) and increase their homeostatic mitotic activity to compensate for the gradual depletion of their population (Shook et al., 2012), properties that confer to the niche a level of resistance to ageing. Significant questions remain to be addressed concerning the exact role of SEZ-driven oligodendrogenesis under physiological and pathological conditions. It is certainly possible that the role of the SEZ falls into both the above-stated hypotheses with not only a role in rejuvenating the adult parenchymal pool of OPCs, but also constantly responding to various environmental cues by providing a cellular boost to the areas in need. There is a definite necessity for a better understanding of adult human oligodendrogenesis and neurogenesis and whether age-related brain pathology is strongly linked to defects in the neurogenic niches.