Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami School of Medicine, Miami, FL 33136, United States.
Department of Human Genetics, University of Miami School of Medicine, Miami, FL 33136, United States.
Exp Neurol. 2018 Oct;308:72-79. doi: 10.1016/j.expneurol.2018.07.001. Epub 2018 Jul 3.
The glial scar is comprised of a heterogeneous population of reactive astrocytes. NG2 glial cells (also known as oligodendrocyte progenitor cells or polydendrocytes) may contribute to this heterogeneity by differentiating into astrocytes in the injured CNS, but there have been conflicting reports about whether astrocytes comprise a significant portion of the NG2 cell lineage. By using genetic fate mapping after spinal cord injury (SCI) and experimental autoimmune encephalomyelitis (EAE) in mice, the goal of this study was to confirm and extend upon previous findings, which have shown that NG2 cell plasticity varies across CNS injuries. We generated mice that express tdTomato in NG2 lineage cells and express GFP under the Aldh1l1 or Glt1 promoter so that NG2 glia-derived astrocytes can be detected by their expression of GFAP and/or GFP. We found that astrocytes comprise approximately 25% of the total NG2 cell lineage in the glial scar by 4 weeks after mid-thoracic contusive SCI, but only 9% by the peak of functional deficit after EAE. Interestingly, a subpopulation of astrocytes expressed only GFP without co-expression of GFAP, uncovering their heterogeneity and the possibility of an underestimation of NG2 glia-derived astrocytes in previous studies. Additionally, we used high performance liquid chromatography to measure the level of tamoxifen and its metabolites in the spinal cord and show that genetic labeling of NG2 glia-derived astrocytes is not an artifact of residual tamoxifen. Overall, our data demonstrate that a heterogeneous population of astrocytes are derived from NG2 glia in an injury type-dependent manner.
胶质瘢痕由反应性星形胶质细胞组成。NG2 神经胶质细胞（也称为少突胶质前体细胞或多形胶质细胞）可能通过在中枢神经系统损伤中分化为星形胶质细胞来导致这种异质性，但关于星形胶质细胞是否构成 NG2 细胞谱系的重要部分存在相互矛盾的报道。通过在脊髓损伤 (SCI) 和实验性自身免疫性脑脊髓炎 (EAE) 后使用遗传命运图谱在小鼠中进行研究，本研究的目的是证实并扩展先前的发现，即 NG2 细胞的可塑性在中枢神经系统损伤中有所不同。我们生成了在 NG2 谱系细胞中表达 tdTomato 并在 Aldh1l1 或 Glt1 启动子下表达 GFP 的小鼠，以便通过表达 GFAP 和/或 GFP 来检测 NG2 胶质细胞衍生的星形胶质细胞。我们发现，在中胸段挫伤性 SCI 后 4 周，星形胶质细胞约占胶质瘢痕中总 NG2 细胞谱系的 25%，但在 EAE 后的功能缺陷高峰期仅占 9%。有趣的是，一部分星形胶质细胞仅表达 GFP 而不共表达 GFAP，揭示了它们的异质性和以前研究中对 NG2 胶质细胞衍生的星形胶质细胞的低估的可能性。此外，我们使用高效液相色谱法测量了脊髓中他莫昔芬及其代谢物的水平，并表明 NG2 胶质细胞衍生的星形胶质细胞的遗传标记不是残留他莫昔芬的人为产物。总体而言，我们的数据表明，以损伤类型依赖的方式，由 NG2 胶质细胞衍生的异质星形胶质细胞群体。
