Diffuse axonal injury (DAI) is an extremely common type of traumatic brain injury encountered in motor vehicle crashes, sports injuries, and in combat. Although many cases of DAI result in chronic disability, there are no current treatments for this condition. Its basic lesion, traumatic axonal injury (TAI), has been aggressively modeled in primate and rodent animal models. The inexorable axonal and perikaryal degeneration and dysmyelination often encountered in TAI 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 (hOPCs) can replace or remodel myelin and, eventually, contribute to axonal regeneration in TAI.
We derived hOPCs from the human embryonic stem cell line H9, purified and characterized them. We then transplanted these hOPCs into the deep sensorimotor cortex next to the corpus callosum of nude rats subjected to TAI 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.
At the time of transplantation, over 90 % of hOPCs 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 OPCs 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, hOPCs progressively matured into MBP (+) and APC (+) oligodendrocytes. The injured environment in the corpus callosum of impact acceleration subjects tended to favor maturation of hOPCs. Electron microscopy revealed that mature transplant-derived oligodendrocytes ensheathed host axons with spiral wraps intimately associated with myelin sheaths.
Our findings suggest that, instead of differentiating locally, hOPCs migrate massively along white matter tracts and differentiate extensively into ensheathing oligodendrocytes. These features make them appealing candidates for cellular therapies of DAI aiming at myelin remodeling and axonal protection or regeneration.