Transmembrane Protein 108 Inhibits the Proliferation and Myelination of Oligodendrocyte Lineage Cells in the Corpus Callosum

Background: Abnormal white matter is a common neurobiological change in bipolar disorder, and dysregulation of myelination in oligodendrocytes is the cause. Transmembrane protein 108 (Tmem108), as a susceptible gene of bipolar disorder, is expressed higher in oligodendrocyte lineage cells than any other lineage cells in the central nervous system. Moreover, Tmem108 mutant mice exhibit mania-like behaviors, belonging to one of the signs of bipolar disorder. However, it is unknown whether Tmem108 regulates myelination of the oligodendrocytes.Results: Tmem108 expression in the corpus callosum decreased with the development, and hypermyelination of the corpus callosum was found in Tmem108 mutant mice, accompanying high expression of myelin basic protein. Strikingly, both oligodendrocyte progenitor cell proliferation and oligodendrocyte myelination were enhanced in the mutant mice. Furthermore, the mutant mice exhibited mania-like behavior after acute restraint stress and were susceptible to drug-induced epilepsy. Conclusions: Tmem108 inhibited oligodendrocyte progenitor cell proliferation and mitigated oligodendrocyte maturation in the corpus callosum, which may also provide a new role of Tmem108 involving bipolar disorder pathogenesis.

IL-17 Inhibits Oligodendrocyte Progenitor Cell Proliferation and Differentiation by Increasing K+ Channel Kv1.3

Interleukin 17 (IL-17) is a signature cytokine of Th17 cells. IL-17 level is significantly increased in inflammatory conditions of the CNS, including but not limited to post-stroke and multiple sclerosis. IL-17 has been detected direct toxicity on oligodendrocyte (Ol) lineage cells and inhibition on oligodendrocyte progenitor cell (OPC) differentiation, and thus promotes myelin damage. The cellular mechanism of IL-17 in CNS inflammatory diseases remains obscure. Voltage-gated K+ (Kv) channel 1.3 is the predominant Kv channel in Ol and potentially involved in Ol function and cell cycle regulation. Kv1.3 of T cells involves in immunomodulation of inflammatory progression, but the role of Ol Kv1.3 in inflammation-related pathogenesis has not been fully investigated. We hypothesized that IL-17 induces myelin injury through Kv1.3 activation. To test the hypothesis, we studied the involvement of OPC/Ol Kv1.3 in IL-17-induced Ol/myelin injury in vitro and in vivo. Kv1.3 currents and channel expression gradually decreased during the OPC development. Application of IL-17 to OPC culture increased Kv1.3 expression, leading to a decrease of AKT activation, inhibition of proliferation and myelin basic protein reduction, which were prevented by a specific Kv1.3 blocker 5-(4-phenoxybutoxy) psoralen. IL-17-caused myelin injury was validated in LPC-induced demyelination mouse model, particularly in corpus callosum, which was also mitigated by aforementioned Kv1.3 antagonist. IL-17 altered Kv1.3 expression and resultant inhibitory effects on OPC proliferation and differentiation may by interrupting AKT phosphorylating activation. Taken together, our results suggested that IL-17 impairs remyelination and promotes myelin damage by Kv1.3-mediated Ol/myelin injury. Thus, blockade of Kv1.3 as a potential therapeutic strategy for inflammatory CNS disease may partially attribute to the direct protection on OPC proliferation and differentiation other than immunomodulation.

Exogenous Oligodendrocyte Progenitor Cell Transplantation Results in Structural and Functional Recovery in a Preterm Infant Cerebral White Matter Injury Rat Model

BackgroundCerebral white matter injury (WMI) is the most common brain injury in preterm infants; it leads to motor and developmental deficits and is often accompanied by cognitive impairment. WMI is characterized by the loss of pre-myelinating oligodendrocytes. Regeneration therapies for preterm neonates with WMI are still in the preclinical phase, among which oligodendrocyte progenitor cell (OPC) transplantation is a promising approach. One promising approach for treating preterm infants is cell replacement therapy, in which lost cells are replaced by human OPCs (hOPCs) derived from human neural stem cells (hNSCs). MethodsIn this study, we developed a method to induce the differentiation of hNSCs into hOPCs. OLIG2+/NG2+/PDGFRα+/O4+ hOPCs were enriched and transplanted into the corpus callosum of a preterm infant WMI rat model. ResultsTransplanted hOPCs survived and migrated throughout the major white matter tracts. Morphological differentiation of transplanted hOPCs was observed. Histology and Magnetic resonance imaging (MRI) revealed lesioned structural repair. Electron microscopy revealed the re-myelination of the axons in the corpus callosum. The Morris water maze test revealed a recovery of cognitive function. ConclusionsOur study showed that transplantation of hOPCs derived from hNSCs is a viable therapeutic strategy for cerebral WMI. The results of our study contribute to the further development of cell therapeutic strategies.