Xu Leyan, Ryu Jiwon, Hiel Hakim, Menon Adarsh, Aggarwal Ayushi, Rha Elizabeth, Mahairaki Vasiliki, Cummings Brian J, Koliatsos Vassilis E
Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Stem Cell Res Ther. 2015 May 14;6(1):93. doi: 10.1186/s13287-015-0087-0.
Diffuse 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.
We 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.
At 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.
Our 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.
弥漫性轴索损伤是机动车碰撞、运动损伤和战斗中常见的一种创伤性脑损伤类型。尽管许多弥漫性轴索损伤病例会导致慢性残疾，但目前尚无针对这种病症的治疗方法。其基本病变，即创伤性轴索损伤，已在灵长类和啮齿类动物模型中得到积极模拟。创伤性轴索损伤中经常出现的轴突和胞体不可避免的变性及脱髓鞘现象需要再生疗法，包括基于干细胞和前体细胞的疗法。在此，我们探讨基于人少突胶质前体细胞移植的治疗方法能否替代或重塑髓鞘，并最终促进创伤性轴索损伤中的轴突再生这一概念的证据。
我们从人胚胎干细胞系H9中分离出人少突胶质前体细胞，对其进行纯化和鉴定。然后，我们将这些人少突胶质前体细胞移植到基于 Marmarou 撞击加速模型遭受创伤性轴索损伤的裸鼠胼胝体旁的深部感觉运动皮层中。我们探究了这些细胞在大鼠前脑分化和结构整合的时间进程及空间分布。
移植时，超过90%的人少突胶质前体细胞表达A2B5、PDGFR、NG2、O4、Olig2和Sox10，这一特征与它们的前体细胞或早期少突胶质细胞状态一致。移植后，这些细胞存活良好，并在受伤和未受伤的大脑中通过胼胝体大量迁移。人少突胶质前体细胞对白质束表现出明显的偏好，几乎完全存在于胼胝体、外囊、纹状体苍白球纹以及皮质第6层。在3个月的时间里，人少突胶质前体细胞逐渐成熟为髓鞘碱性蛋白(+)和腺瘤性息肉病蛋白(+)的少突胶质细胞。撞击加速实验对象胼胝体中的损伤环境倾向于促进人少突胶质前体细胞的成熟。电子显微镜显示，成熟的移植来源的少突胶质细胞用与髓鞘紧密相关的螺旋状包裹物包裹宿主轴突。
我们的研究结果表明，人少突胶质前体细胞并非在局部分化，而是沿着白质束大量迁移并广泛分化为包裹性少突胶质细胞。这些特性使其成为针对弥漫性轴索损伤进行髓鞘重塑以及轴突保护或再生的细胞疗法的有吸引力的候选者。
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