Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON M5T 2S8, Canada.
Centre for Functional and Metabolic Mapping, Robarts Research Institute, the University of Western Ontario, London, ON, N6A 5B7, Canada.
eNeuro. 2018 Dec 4;5(5). doi: 10.1523/ENEURO.0369-18.2018. eCollection 2018 Sep-Oct.
Cerebral palsy (CP) is a common pediatric neurodevelopmental disorder, frequently resulting in motor and developmental deficits and often accompanied by cognitive impairments. A regular pathobiological hallmark of CP is oligodendrocyte maturation impairment resulting in white matter (WM) injury and reduced axonal myelination. Regeneration therapies based on cell replacement are currently limited, but neural precursor cells (NPCs), as cellular support for myelination, represent a promising regeneration strategy to treat CP, although the transplantation parameters (e.g., timing, dosage, mechanism) remain to be determined. We optimized a hemiplegic mouse model of neonatal hypoxia-ischemia that mirrors the pathobiological hallmarks of CP and transplanted NPCs into the corpus callosum (CC), a major white matter structure impacted in CP patients. The NPCs survived, engrafted, and differentiated morphologically in male and female mice. Histology and MRI showed repair of lesioned structures. Furthermore, electrophysiology revealed functional myelination of the CC (e.g., restoration of conduction velocity), while cylinder and CatWalk tests demonstrated motor recovery of the affected forelimb. Endogenous oligodendrocytes, recruited in the CC following transplantation of exogenous NPCs, are the principal actors in this recovery process. The lack of differentiation of the transplanted NPCs is consistent with enhanced recovery due to an indirect mechanism, such as a trophic and/or "bio-bridge" support mediated by endogenous oligodendrocytes. Our work establishes that transplantation of NPCs represents a viable therapeutic strategy for CP treatment, and that the enhanced recovery is mediated by endogenous oligodendrocytes. This will further our understanding and contribute to the improvement of cellular therapeutic strategies.
脑性瘫痪（CP）是一种常见的小儿神经发育障碍，常导致运动和发育缺陷，常伴有认知障碍。CP 的一个常见的病理生物学特征是少突胶质细胞成熟受损，导致白质（WM）损伤和轴突髓鞘形成减少。基于细胞替代的再生疗法目前受到限制，但神经前体细胞（NPCs）作为髓鞘形成的细胞支持，代表了治疗 CP 的一种有前途的再生策略，尽管移植参数（例如，时间、剂量、机制）仍有待确定。我们优化了一种新生鼠缺氧缺血性偏瘫模型，该模型模拟了 CP 的病理生物学特征，并将 NPC 移植到胼胝体（CC）中，CC 是 CP 患者受影响的主要白质结构。NPC 在雄性和雌性小鼠中存活、植入并在形态上分化。组织学和 MRI 显示受损结构得到修复。此外，电生理学显示 CC 的功能髓鞘形成（例如，传导速度的恢复），而圆筒和 CatWalk 测试显示受影响前肢的运动恢复。移植外源性 NPC 后，CC 中募集的内源性少突胶质细胞是恢复过程中的主要因素。移植 NPC 不分化与增强恢复一致，增强恢复的原因是间接机制，例如由内源性少突胶质细胞介导的营养和/或“生物桥”支持。我们的工作表明 NPC 移植代表了治疗 CP 的一种可行的治疗策略，并且增强的恢复是由内源性少突胶质细胞介导的。这将进一步加深我们对这一过程的理解，并有助于改善细胞治疗策略。
