Transient receptor potential melastatin 2 expression is increased following experimental traumatic brain injury in rats

Traumatic brain injury (TBI) elicits a sequence of complex biochemical changes including oxidative stress, oedema, inflammation and excitotoxicity. These factors contribute to the high morbidity and mortality following TBI, although their underlying molecular mechanisms remain poorly understood. Transient receptor potential melastatin 2 (TRPM2) is a non-selective cation channel, highly expressed in the brain and immune cells. Recent studies have implicated TRPM2 channels in processes involving oxidative stress, inflammation and cell death. However, no studies have investigated the role of TRPM2 in TBI pathophysiology. In the present study, we have characterised TRPM2 mRNA and protein expression following experimental TBI. Adult male Sprague Dawley rats were injured using the impact-acceleration model of diffuse TBI with survival times between 5 and 5 days. Real-time RT-PCR (including reference gene validation studies) and semi-quantitative immunohistochemistry were used to quantify TRPM2 mRNA and protein levels, respectively, following TBI. Significant increases in TRPM2 mRNA and protein expression were observed in the cerebral cortex and hippocampus of injured animals, suggesting that TRPM2 may contribute to TBI injury processes such as oxidative stress, inflammation and neuronal death. Further characterisation of how TRPM2 may contribute to TBI pathophysiology is warranted.Naomi L. Cook, Robert Vink, Stephen C. Helps, Jim Manavis and Corinna van den Heuve

Transplantation of human oligodendrocyte progenitor cells in an animal model of diffuse traumatic axonal injury: survival and differentiation.

IntroductionDiffuse axonal injury is an extremely common type of traumatic brain injury encountered in motor vehicle crashes, sports injuries, and in combat. Although many cases of diffuse axonal injury result in chronic disability, there are no current treatments for this condition. Its basic lesion, traumatic axonal injury, has been aggressively modeled in primate and rodent animal models. The inexorable axonal and perikaryal degeneration and dysmyelination often encountered in traumatic axonal injury calls for regenerative therapies, including therapies based on stem cells and precursors. Here we explore the proof of concept that treatments based on transplants of human oligodendrocyte progenitor cells can replace or remodel myelin and, eventually, contribute to axonal regeneration in traumatic axonal injury.MethodsWe derived human oligodendrocyte progenitor cells from the human embryonic stem cell line H9, purified and characterized them. We then transplanted these human oligodendrocyte progenitor cells into the deep sensorimotor cortex next to the corpus callosum of nude rats subjected to traumatic axonal injury based on the impact acceleration model of Marmarou. We explored the time course and spatial distribution of differentiation and structural integration of these cells in rat forebrain.ResultsAt the time of transplantation, over 90 % of human oligodendrocyte progenitor cells expressed A2B5, PDGFR, NG2, O4, Olig2 and Sox10, a profile consistent with their progenitor or early oligodendrocyte status. After transplantation, these cells survived well and migrated massively via the corpus callosum in both injured and uninjured brains. Human oligodendrocyte progenitor cells displayed a striking preference for white matter tracts and were contained almost exclusively in the corpus callosum and external capsule, the striatopallidal striae, and cortical layer 6. Over 3 months, human oligodendrocyte progenitor cells progressively matured into myelin basic protein(+) and adenomatous polyposis coli protein(+) oligodendrocytes. The injured environment in the corpus callosum of impact acceleration subjects tended to favor maturation of human oligodendrocyte progenitor cells. Electron microscopy revealed that mature transplant-derived oligodendrocytes ensheathed host axons with spiral wraps intimately associated with myelin sheaths.ConclusionsOur findings suggest that, instead of differentiating locally, human oligodendrocyte progenitor cells migrate massively along white matter tracts and differentiate extensively into ensheathing oligodendrocytes. These features make them appealing candidates for cellular therapies of diffuse axonal injury aiming at myelin remodeling and axonal protection or regeneration