Department of Molecular Biology and Biochemistry, Sue and Bill Gross Stem Cell Center, and Institute for Immunology, University of California, Irvine, CA 92697, USA.
Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):11068-73. doi: 10.1073/pnas.1006375107. Epub 2010 Jun 1.
Multiple sclerosis (MS) is a human demyelinating disease characterized by multifocal regions of inflammation, progressive myelin loss within the central nervous system (CNS), and eventual failure to remyelinate damaged axons. These problems suggest deficiencies in recruiting and/or maturation of oligodendrocyte progentior cells (OPCs) and highlight cell replacement therapies to promote remyelination. We have used a model of viral-induced demyelination to characterize signaling cues associated with positional migration of transplanted remyelination-competent cells. Although successful transplantation of rodent-derived glial cell types into models of MS has been performed, the mechanisms by which these cells navigate within an inflammatory environment created by a persistent virus has not been defined. Infection of the mouse CNS with the neurotropic JHM strain of mouse hepatitis virus (JHMV) results in an immune-mediated demyelinating disease with clinical and histologic similarities to MS. Surgical engraftment of GFP+ neural stem cells (NSCs) into spinal cords of JHMV-infected mice with established demyelination results in migration, proliferation, and differentiation of the cells into OPCs and mature oligodendrocytes that is associated with increased axonal remyelination. Treatment with anti-CXCL12 [stromal derived factor-1alpha, (SDF-1alpha)] blocking serum resulted in a marked impairment in migration and proliferation of engrafted stem cells. Moreover, small molecule-mediated antagonism of CXCR4, but not CXCR7, impaired migration and proliferation, to an extent similar to that with anti-CXCL12 treatment. These data highlight the importance of the CXCL12:CXCR4 pathway in regulating homing of engrafted stem cells to sites of tissue damage within the CNS of mice persistently infected with a neurotropic virus undergoing immune-mediated demyelination.
多发性硬化症（MS）是一种人类脱髓鞘疾病，其特征是中枢神经系统（CNS）中有多个炎症部位、髓鞘渐进性丢失，最终导致受损轴突无法再髓鞘化。这些问题表明少突胶质前体细胞（OPC）的募集和/或成熟存在缺陷，并突出了细胞替代疗法以促进髓鞘再生。我们使用病毒诱导的脱髓鞘模型来描述与移植的髓鞘再生能力细胞的位置迁移相关的信号线索。虽然已经成功地将啮齿动物衍生的神经胶质细胞类型移植到 MS 模型中，但这些细胞在由持续性病毒引起的炎症环境中导航的机制尚未确定。用嗜神经的 JHM 株鼠肝炎病毒（JHMV）感染小鼠中枢神经系统会导致免疫介导的脱髓鞘疾病，其临床和组织学特征与 MS 相似。将 GFP+神经干细胞（NSCs）移植到已建立脱髓鞘的 JHMV 感染小鼠的脊髓中，会导致细胞迁移、增殖并分化为少突胶质前体细胞和成熟的少突胶质细胞，从而增加轴突的髓鞘再生。用抗 CXCL12 [基质衍生因子-1α（SDF-1α）]阻断血清治疗会导致移植的干细胞的迁移和增殖明显受损。此外，小分子介导的 CXCR4 拮抗作用，但不是 CXCR7，会损害迁移和增殖，其程度与抗 CXCL12 治疗相似。这些数据突出了 CXCL12:CXCR4 途径在调节移植的干细胞向持续感染神经嗜性病毒并发生免疫介导脱髓鞘的小鼠 CNS 中组织损伤部位归巢的重要性。
