SummaryThe age-related failure to produce oligodendrocytes from oligodendrocyte progenitor cells (OPCs) is associated with irreversible neurodegeneration in multiple sclerosis (MS). Consequently, regenerative approaches have significant potential for treating chronic demyelinating diseases. Here, we show that the differentiation potential of adult rodent OPCs decreases with age. Aged OPCs become unresponsive to pro-differentiation signals, suggesting intrinsic constraints on therapeutic approaches aimed at enhancing OPC differentiation. This decline in functional capacity is associated with hallmarks of cellular aging, including decreased metabolic function and increased DNA damage. Fasting or treatment with metformin can reverse these changes and restore the regenerative capacity of aged OPCs, improving remyelination in aged animals following focal demyelination. Aged OPCs treated with metformin regain responsiveness to pro-differentiation signals, suggesting synergistic effects of rejuvenation and pro-differentiation therapies. These findings provide insight into aging-associated remyelination failure and suggest therapeutic interventions for reversing such declines in chronic disease.

Oligodendrocyte loss in neurological disease leaves axons vulnerable to damage and degeneration, and activity-dependent myelination may represent an endogenous mechanism to improve remyelination following injury. Here, we report that while learning a forelimb reach task transiently suppresses oligodendrogenesis, it subsequently increases OPC differentiation, oligodendrocyte generation, and myelin sheath remodeling in the forelimb motor cortex. Immediately followingdemyelination, neurons exhibit hyperexcitability, learning is impaired, and behavioral intervention provides no benefit to remyelination. However, partial remyelination restores neuronal and behavioral function allowing learning to enhance oligodendrogenesis, remyelination of denuded axons, and the ability of surviving oligodendrocytes to generate new myelinsheaths. Previously considered controversial, we show that sheath generation by mature oligodendrocytes is not only possible but also increases myelin pattern preservation following demyelination, presenting a new target for therapeutic interventions. Together, our findings demonstrate that precisely-timed motor learning improves recovery from demyelinating injury via enhanced remyelination from new and surviving oligodendrocytes.

Experimental models of myelin disorders can be treated by the transplantation of oligodendrocyte progenitor cells (OPCs) into the affected brain or spinal cord. OPCs express gangliosides recognized by MAb A2B5, but this marker also identifies lineage-restricted astrocytes and immature neurons. To establish a more efficient means of isolating myelinogenic OPCs, we asked if FACS could be used to sort PDGFα receptor+ cells from fetal human forebrain, based on expression of the PDGFRα epitope CD140a. CD140a+ isolates were maintained as mitotic bipotential progenitors that could be instructed to either oligodendrocyte or astrocyte fate. Transplanted CD140a+ cells were highly migratory, and rapidly and robustly myelinated the hypomyelinated shiverer mouse brain, more efficiently than did A2B5-sorted cells. Microarray analysis of CD140a+ cells revealed their differential expression of CD9, as well as of PTN-PTPRZ1, wnt, notch and BMP pathway components, indicating the dynamic interaction of self-renewal and fate-restricting pathways in these cells.

Embryonic stem cells (ESCs) self-renew in a state of naïve pluripotency in which they are competent to generate all somatic cells 1 . It has been hypothesized that, before irreversibly committing, ESCs pass through at least one metastable transition state 2-4 . This transition would represent a gateway for differentiation and reprogramming of somatic cells 5,6 . We sought a mechanical phenotype of transition by probing the nuclear response to compressive and tensile forces and found that, during transition, nuclei of ESCs are auxetic: they displayed a crosssectional expansion when stretched and a cross-sectional contraction when compressed, and their stiffness increased under compression. We show that the auxetic phenotype of transition ESC nuclei is driven at least in part by global chromatin decondensation. Through the regulation of molecular turnover in the differentiating nucleus by external forces, auxeticity could be a key element in mechanotransduction. Our findings highlight the importance of nuclear structure in the regulation of differentiation and reprogramming.Reprints and permissions information is available online at www.nature.com/reprints.