Resetting the Stem Cell Clock

Compelling evidence to date suggests that the complex endothelial network of the central nervous system, initially thought to be an inert plumbing system, is actually a quintessential player in neural stem cell differentiation and thus tissue regeneration of the CNS.1 Located within pockets of tightly controlled microenvironment are oligodendrocyte precursor cells (OPCs) capable of differentiating into remyelinating oligodendrocytes in order to restore the altered myelin sheath while also preventing axonal degeneration in pathogenic states such as multiple sclerosis (MS).2 Aging's imminent tolls3 disrupt the homeostatic mechanism and crosstalk at the level of this putative oligovascular niche delaying or completely impeding the regenerative process, a major draw-back in long term demyelinating diseases such as MS. Whether these inexorable age-dependent effects strictly take place at the microcellular level or more generally impact the systemic milieu with subsequent repercussions on the niche is still under debate.4 Pinpointing specific crosstalk channels and molecular mechanisms directly involved in delivering messages from the systemic medium to the subcellular level is of utmost importance. The innate immune system, through the monocytic-macrophagic component, seems to be one of the main characters in the process by myelin debris phagocytosis.5 Henceforth, an intriguing possibility arises: can resetting the aging clock of OPCs through exposure to youthful exogenous factors and replenishing the macrophage pool, restore remyelination efficiency and mend demyelinating pathogenic processes? However, the question of reversibility of age-related changes has so far been an insurmountable road block in tapping the endogenous source of remyelinating cells and has led to numerous attempts at importing progenitors through various transplant and inoculation methods, with little success to date.6 In their latest study, Ruckh et al (Cell Stem Cell, January 2012)7 seek to elucidate the impact of a youthful systemic environment on the epigenetic changes of aging oligodendrocyte lineage cells in an ultimate attempt to reverse the typical age-associated decline in remyelination and hence to promote functional recovery in demyelinating pathological states. The authors propose a novel experimental model in order to test reactivation of dormant competency of these aged neural stem cells: heterochronic parabiosis, surgically joining aged mice to isogenic young animals in order to continuously flood the system of the former with youthful environmental signals. After confirming cross-circulation with green fluorescent protein (GFP) tagged young cells, by monitoring OPC density at the level of lysolecithin induced demyelinating spinal cord lesions, Ruckh et al showed increasing numbers of oligodendrocyte progenitors as well as CD34+ endothelial cells in heterochronic pairs as compared to isochronic controls. Angiogenesis seems to be an important event in the regulation of oligodendroc yte progenitor proliferation and differentiation. The observed increased density of precursors positively correlated with rising prevalence of Olig2+/CC1+ mature oligodendrocytes which furthermore meant significantly improved remyelination as assessed by semithin resin sections, thus proving the reversal of the age imposed differentiation block. No effect was noted regarding reactive astrocytosis or OPC apoptosis, suggesting alternate environment independent mechanisms. However, by analyzing the absence of GFP+ OPCs in old animals, authors showed that the restoration of the remyelinating process was entirely due to reactivation of the latent aged OPCs, consequently excluding the confounding effect of transplanted young progenitors. Healing of the spinal cord injury was not affected in young animals by the exposure to the aging environmental factors, also excluding the possible dilution role the youthful climate might have played in jump-starting the remyelination process. The authors then proceeded to identifying the pawn that regulates or mediates the rejuvenation process. The inflammatory infiltrate within the toxin induced lesions was primarily comprised of MAC1+ macrophages with trace amounts of CD4+/CD8+ T lymphocytes, B lymphocytes, CD94+ natural killer cells or neutrophils. Containing almost exclusively GFP+ cells, the infiltrate was recruited in its entirety from the young blood stream, raising questions regarding the role of the innate immune system in assisting the remyelination process (See Figure). To pursue this lead, Ruckh et al used CCR2-deficient mice, knocking down the main chemokine receptor for the MCP1 driven chemotaxis process of macrophages and showing massive reductions in the mature oligodendrocyte density in single young deficient mice. Macrophage recruitment is the key regulatory mechanism of the OPC differentiation process. Using the CCR2 deficient young mice in heterochronic pairs significantly lowered the infiltrate build-up at the level of the spinal cord injury in old animals without impeding cross-circulation of other factors, thus proving the existence of 2 equally important but functionally independent pathways in rejuvenation. Co-occurrence of both events is needed to achieve complete OPC differentiation leading to full restoration of saltatory conduction 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 withi