Porambo Michael, Phillips Andre W, Marx Joel, Ternes Kylie, Arauz Edwin, Pletnikov Mikhail, Wilson Mary Ann, Rothstein Jeffery D, Johnston Michael V, Fatemi Ali
Kennedy Krieger Institute, Johns Hopkins University, Baltimore, Maryland.
Glia. 2015 Mar;63(3):452-65. doi: 10.1002/glia.22764. Epub 2014 Nov 6.
Neonatal white matter injury (NWMI) is the leading cause of cerebral palsy and other neurocognitive deficits in prematurely-born children, and no restorative therapies exist. Our objective was to determine the fate and effect of glial restricted precursor cell (GRP) transplantation in an ischemic mouse model of NWMI.
Neonatal CD-1 mice underwent unilateral carotid artery ligation on postnatal-Day 5 (P5). At P22, intracallosal injections of either enhanced green fluorescent protein (eGFP) + GRPs or saline were performed in control and ligated mice. Neurobehavioral and postmortem studies were performed at 4 and 8 weeks post-transplantation.
GRP survival was comparable at 1 month but significantly lower at 2 months post-transplantation in NWMI mice compared with unligated controls. Surviving cells showed better migration capability in controls; however, the differentiation capacity of transplanted cells was similar in control and NWMI. Saline-treated NWMI mice showed significantly altered response in startle amplitude and prepulse inhibition (PPI) paradigms compared with unligated controls, while these behavioral tests were completely normal in GRP-transplanted animals. Similarly, there was significant increase in hemispheric myelin basic protein density, along with significant decrease in pathologic axonal staining in cell-treated NWMI mice compared with saline-treated NWMI animals.
The reduced long-term survival and migration of transplanted GRPs in an ischemia-induced NWMI model suggests that neonatal ischemia leads to long-lasting detrimental effects on oligodendroglia even months after the initial insult. Despite limited GRP-survival, behavioral, and neuropathological outcomes were improved after GRP-transplantation. Our results suggest that exogenous GRPs improve myelination through trophic effects in addition to differentiation into mature oligodendrocytes.
新生儿白质损伤（NWMI）是早产儿童脑瘫和其他神经认知缺陷的主要原因，目前尚无恢复性治疗方法。我们的目的是确定胶质细胞限制前体细胞（GRP）移植在NWMI缺血小鼠模型中的命运和效果。
新生CD-1小鼠在出生后第5天（P5）进行单侧颈动脉结扎。在P22时，对对照小鼠和结扎小鼠进行胼胝体内注射增强型绿色荧光蛋白（eGFP）+GRP或生理盐水。在移植后4周和8周进行神经行为和死后研究。
与未结扎的对照相比，NWMI小鼠移植后1个月时GRP存活率相当，但在2个月时显著降低。存活细胞在对照中显示出更好的迁移能力；然而，移植细胞在对照和NWMI中的分化能力相似。与未结扎的对照相比，生理盐水处理的NWMI小鼠在惊吓幅度和预脉冲抑制（PPI）范式中表现出明显改变的反应，而在GRP移植的动物中这些行为测试完全正常。同样，与生理盐水处理的NWMI动物相比，细胞处理的NWMI小鼠半球髓鞘碱性蛋白密度显著增加，病理轴突染色显著减少。
在缺血诱导的NWMI模型中，移植的GRP长期存活率和迁移率降低，这表明新生儿缺血即使在最初损伤数月后仍会对少突胶质细胞产生长期有害影响。尽管GRP存活有限，但GRP移植后行为和神经病理学结果得到改善。我们的结果表明外源性GRP除了分化为成熟少突胶质细胞外，还通过营养作用改善髓鞘形成。
