NG2-glia as multipotent neural stem cells: fact or fantasy?

Abstract

Cycling glial precursors-"NG2-glia"-are abundant in the developing and mature central nervous system (CNS). During development, they generate oligodendrocytes. In culture, they can revert to a multipotent state, suggesting that they might have latent stem cell potential that could be harnessed to treat neurodegenerative disease. This hope has been subdued recently by a series of fate-mapping studies that cast NG2-glia as dedicated oligodendrocyte precursors in the healthy adult CNS-though rare, neuron production in the piriform cortex remains a possibility. Following CNS damage, the repertoire of NG2-glia expands to include Schwann cells and possibly astrocytes-but so far not neurons. This reaffirms the central role of NG2-glia in myelin repair. The realization that oligodendrocyte generation continues throughout normal adulthood has seeded the idea that myelin genesis might also be involved in neural plasticity. We review these developments, highlighting areas of current interest, contention, and speculation.

Figure 1

Compendium of images of NG2-glia and their differentiated progeny in transgenic mice. (A) Low magnification epifluorescence image of the cerebral cortex of a P13 Sox10-GFP mouse showing the near-uniform distribution of oligodendrocyte lineage cells, mainly NG2-glia (R.B.T. unpublished). (B) A single NG2-glial cell in the cerebellum of a P45 Pdgfra-CreER* : Rosa26-YFP mouse, identified by intrinsic fluorescence in a vibratome section, dye-filled through a micropipet with Alexa Fluor 488 to reveal whole cell morphology and imaged by two-photon microscopy (Rivers et al., 2008; M.Rizzi unpublished). (C) A dye-filled myelinating oligodendrocyte in the corpus callosum of a Pdgfra-CreER* : Rosa26-YFP mouse, induced with tamoxifen at P45 and examined 28 days later (P45+28) in the two-photon microscope (Rivers et al., 2008). This adult-born oligodendrocyes has >50 internodes (D) A myelinating oligodendrocyte in the optic nerve of a Pdgfra-CreER* : Tau-mGFP mouse at P60+28. Membrane-tethered mGFP reveals full cell morphology including the myelin sheaths (K.M.Y. unpublished). (E) A myelinating oligodendrocyte in the cortical grey matter of a Pdgfra-CreER* : Tau-mGFP mouse, showing many short randomly-orientated myelin internodes that contrast with the multiple aligned internodes in white matter (K.M.Y. unpublished). (F) Remyelinating oligodendrocytes in a Pdgfra-CreER* : Rosa26-YFP focally-demyelinated spinal cord (Zawadzka et al., 2010). The mice were induced with tamoxifen on four consecutive days starting at ~P75, lysolecithin (1% v/v) was injected stereotaxically four days after the final dose and the animals were analyzed 3 weeks later by epifluorescence microscopy. Oligodendrocyte cell bodies are visualized with anti-GFP (green) and myelin sheaths with anti-PLP (red). Note that cytoplasmic YFP does not readily enter compact myelin, presumably for steric reasons. (G) Remyelinating Schwann cells within a focal ethidium bromide (0.1% w/v)-induced lesion in Pdgfra-CreER* : Rosa26-YFP spinal cord (Zawadzka et al., 2010). Schwann cells are identified by immunolabelling for the Schwann cell-specific protein Periaxin (red).