Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK.
Wellcome - MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
Nat Commun. 2024 Oct 9;15(1):8570. doi: 10.1038/s41467-024-52444-w.
In Multiple Sclerosis (MS), inflammatory demyelinated lesions in the brain and spinal cord lead to neurodegeneration and progressive disability. Remyelination can restore fast saltatory conduction and neuroprotection but is inefficient in MS especially with increasing age, and is not yet treatable with therapies. Intrinsic and extrinsic inhibition of oligodendrocyte progenitor cell (OPC) function contributes to remyelination failure, and we hypothesised that the transplantation of 'improved' OPCs, genetically edited to overcome these obstacles, could improve remyelination. Here, we edit human(h) embryonic stem cell-derived OPCs to be unresponsive to a chemorepellent released from chronic MS lesions, and transplant them into rodent models of chronic lesions. Edited hOPCs display enhanced migration and remyelination compared to controls, regardless of the host age and length of time post-transplant. We show that genetic manipulation and transplantation of hOPCs overcomes the negative environment inhibiting remyelination, with translational implications for therapeutic strategies for people with progressive MS.
在多发性硬化症 (MS) 中，大脑和脊髓中的炎症性脱髓鞘病变导致神经退行性变和进行性残疾。髓鞘再生可以恢复快速跳跃传导和神经保护作用，但在 MS 中效率不高，特别是随着年龄的增长，并且目前还没有针对这种疾病的治疗方法。少突胶质前体细胞 (OPC) 功能的内在和外在抑制导致髓鞘再生失败，我们假设移植“改良”的 OPC 可以克服这些障碍，从而改善髓鞘再生。在这里，我们编辑人源胚胎干细胞衍生的 OPC，使其对慢性 MS 病变释放的趋化抑制因子无反应，并将其移植到慢性病变的啮齿动物模型中。与对照组相比，编辑后的 hOPC 显示出增强的迁移和髓鞘再生能力，而与宿主年龄和移植后时间无关。我们表明，hOPC 的遗传操作和移植克服了抑制髓鞘再生的负性环境，为进展性 MS 患者的治疗策略提供了转化意义。
