Institute for Pediatric Regenerative Medicine, University of California, Davis, School of Medicine and Shriners Hospital, Sacramento, California 95817, USA.
J Neurosci. 2011 Aug 17;31(33):11914-28. doi: 10.1523/JNEUROSCI.1759-11.2011.
Accumulations of hypertrophic, intensely glial fibrillary acidic protein-positive (GFAP(+)) astroglia, which also express immunoreactive nestin and vimentin, are prominent features of multiple sclerosis lesions. The issues of the cellular origin of hypertrophic GFAP(+)/vimentin(+)/nestin(+) "reactive" astroglia and also the plasticities and lineage relationships among three macroglial progenitor populations-oligodendrocyte progenitor cells (OPCs), astrocytes and ependymal cells-during multiple sclerosis and other CNS diseases remain controversial. We used genetic fate-mappings with a battery of inducible Cre drivers (Olig2-Cre-ER(T2), GFAP-Cre-ER(T2), FoxJ1-Cre-ER(T2) and Nestin-Cre-ER(T2)) to explore these issues in adult mice with myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis (EAE). The proliferative rate of spinal cord OPCs rose fivefold above control levels during EAE, and numbers of oligodendroglia increased as well, but astrogenesis from OPCs was rare. Spinal cord ependymal cells, previously reported to be multipotent, did not augment their low proliferative rate, nor give rise to astroglia or OPCs. Instead, the hypertrophic, vimentin(+)/nestin(+), reactive astroglia that accumulated in spinal cord in this multiple sclerosis model were derived by proliferation and phenotypic transformation of fibrous astroglia in white matter, and solely by phenotypic transformation of protoplasmic astroglia in gray matter. This comprehensive analysis of macroglial plasticity in EAE helps to clarify the origins of astrogliosis in CNS inflammatory demyelinative disorders.
在多发性硬化症病变中，增生的、强烈胶质纤维酸性蛋白阳性（GFAP(+)）星形胶质细胞的积累是显著特征，这些星形胶质细胞也表达免疫反应性巢蛋白和波形蛋白。增生的 GFAP(+)/波形蛋白（+）/巢蛋白（+）“反应性”星形胶质细胞的细胞起源问题，以及在多发性硬化症和其他中枢神经系统疾病中三种大胶质前体细胞——少突胶质前体细胞（OPC）、星形胶质细胞和室管膜细胞——之间的可塑性和谱系关系仍然存在争议。我们使用了一系列诱导型 Cre 驱动基因（Olig2-Cre-ER(T2)、GFAP-Cre-ER(T2)、FoxJ1-Cre-ER(T2)和 Nestin-Cre-ER(T2)）的遗传命运图谱，来研究在髓鞘少突胶质糖蛋白肽诱导的实验性自身免疫性脑脊髓炎（EAE）的成年小鼠中这些问题。EAE 期间，脊髓 OPC 的增殖率比对照水平增加了五倍，少突胶质细胞的数量也增加了，但 OPC 很少发生星形胶质细胞生成。以前报道为多能性的脊髓室管膜细胞并没有增加其低增殖率，也没有产生星形胶质细胞或 OPC。相反，在这个多发性硬化症模型中，脊髓中积累的增生的、波形蛋白（+）/巢蛋白（+）、反应性星形胶质细胞是由白质中纤维星形胶质细胞的增殖和表型转化而来，仅由灰质中原浆星形胶质细胞的表型转化而来。对 EAE 中大胶质细胞可塑性的全面分析有助于阐明中枢神经系统炎症脱髓鞘疾病中星形胶质细胞增生的起源。
