NG2 glial cells regulate neuroimmunological responses to maintain neuronal function and survival

Abstract

NG2-expressing neural progenitor cells (i.e., NG2 glial cells) maintain their proliferative and migratory activities even in the adult mammalian central nervous system (CNS) and produce myelinating oligodendrocytes and astrocytes. Although NG2 glial cells have been observed in close proximity to neuronal cell bodies in order to receive synaptic inputs, substantive non-proliferative roles of NG2 glial cells in the adult CNS remain unclear. In the present study, we generated NG2-HSVtk transgenic rats and selectively ablated NG2 glial cells in the adult CNS. Ablation of NG2 glial cells produced defects in hippocampal neurons due to excessive neuroinflammation via activation of the interleukin-1 beta (IL-1β) pro-inflammatory pathway, resulting in hippocampal atrophy. Furthermore, we revealed that the loss of NG2 glial cell-derived hepatocyte growth factor (HGF) exacerbated these abnormalities. Our findings suggest that NG2 glial cells maintain neuronal function and survival via the control of neuroimmunological function.

NG2 Glia: Novel Roles beyond Re-/Myelination

“…However, even in those regions where NG2 ablation reached higher percentages (i.e., 80% in the subcortical white matter and 90% in the striatum after seven days), no sign of neurodegeneration was detected in NG2Cre-R26DTR mice. An alternative explanation could be that the huge mass of NG2 glia simultaneously undergoing cell death in [88] may have triggered a robust microglia response that eventually impacted on hippocampal neuron survival per se (i.e., independently of the possible effects of NG2 glia loss); further studies will clarify this issue. In any case, the inconsistency of the results of these two studies points to the intrinsic limitations of all cell ablation approaches, that must be taken into account in the interpretation of the results obtained by these experimental strategies.…”

“…Reduced levels of the immunomodulatory factor hepatocyte growth factor (HGF) have been proposed to mediate such effects. The different outcomes of NG2 glia ablation in the two studies may be interpreted again as the result of the loss of region-specific functions exerted by NG2 glia, or may be related to the different extent and timing of cell ablation (about 50% of NG2 glia in the cortex after seven days in [87]; about 80% in the hippocampus after one day in [88]). Milder effects reported in Birey et al [87] may be indicative of the persistence of a sufficient number of NG2 glia contributing to neuronal support in the mouse cortex.…”

“…Conversely, in a transgenic rat model expressing thymidine kinase (TK) (that converts the prodrug ganciclovir into a toxic triphosphate molecule that can be incorporated into the genome during DNA synthesis, leading to the selective ablation of proliferative cells) under the NG2 promoter, Nakano et al [88] found that NG2 glia loss induced neurodegeneration, microglia activation and neuroinflammation in the adult hippocampus. Reduced levels of the immunomodulatory factor hepatocyte growth factor (HGF) have been proposed to mediate such effects.…”

“…study of cultured mouse NG2 glia [87]; Gene expr. study and CM of cultured rat NG2 glia [93] Neuronal and glial cell survival [88,188]. Anti-inflammatory functions [189] Transforming growth factor beta, Tgf-b…”

“…study of cultured rat NG2 glia [93] Synaptic maturation [110] Hepatocyte growth factor, HGF In vivo expr. in rat NG2 glia [88]; Protein expr. in cultured rat NG2 glia [111] Neuronal plasticity [112] Neurotrophins Brain derived growth factor, BDNF CM of cultured rat NG2 glia and protein expr.…”