and preventing axonal degeneration by attenuating myelin degradation in MS-like disease states. Authors then sought to shed light on the exact mechanism of macrophage influence on the remyelination process. Macrophage secreted growth factors, including IGF-1 and PDGF-1A, as well as immune-modulatory cytokines, systemic mediators in tissue regeneration, could not be identified as a valid pathway for directly controlling OPC fate. This is further proof that the systemic environment, while capable of modulating and facilitating stem cell differentiation to a certain extent, cannot definitively override the tightly regulated microenvironment within the stem cell niche. Rather than grossly systemic modulation, the decisive role played by macrophages in the remyelination process seems to be honed in on the stem cell microenvironment: fine-tuning OPC maturation by releasing the inhibitory break of myelin products through CCR2-dependent debris clearance. Contained within the confinements and strict control of their microenvironment, the oligovascularniche,OPCs are still susceptible to a certain extent to the modulating effects of external systemic factors. Epigenetic age related attenuation of OPC differentiation and remyelinating capacity seems to be reversible by exposure to a youthful systemic climate thus making the potentiation of the progenitor response through exogenous factors an appealing future therapeutic strategy in demyelinating disorders. Specific soluble factors, such as leukemia inhibitory factor, capable of crossing from the systemic circulation to the neurovascular niche in order to directly guide stem cell fate and thus bridging the macro and the microenvironment, are still under investigation. However, the role of the vascular network as delivery pipeline for immune cells and the role of the endothelium per se, as the main crosstalk partner in the process of remyelination and tissue regeneration, are becoming increasingly clear. While the full cast of actors involved in this complex process of CNS regeneration is yet to be completely revealed, effective remyelinating therapies might indeed become reality once all the pieces of the puzzle have come together.