Extensive regenerative plasticity among adult NG2-glia populations is exclusively based on self-renewal

Abstract

NG2-glia are known to proliferate in the adult brain, however the extent of their mitotic and regenerative capacity and particularly their adult origin is uncertain. By employing a paradigm of mitotic blockade in conjunction with genetic fate tracing we demonstrate that intracerebroventricular mitotic blocker infusion leads to wide-spread and complete ablation of NG2-glial cells in the hypothalamus and other periventricular brain regions. However, despite the extensive glia loss, parenchymal NG2-glia coverage is fully restored to pretreatment levels within two weeks. We further reveal that in response to mitotic blocker treatment, NG2-glia bordering the ablated territories start to express the stem cell marker nestin, divide and migrate to replace the lost cells. Importantly, the migration front of repopulating NG2-glia invariably proceeds from the distal parenchyma towards the ventricles, ruling out contributions of the subventricular zone neurogenic niche or the corresponding area of the third ventricle as source of new NG2-glia. NG2-CreER-based fate tracing further substantiates that NG2-glia which have been spared from mitotic blockade are the sole source of regenerating NG2-glia. Collectively, our data reveals that all adult NG2-glia retain the ability to divide and that they are capable of fully restoring parenchymal NG2-glia coverage after wide-spread NG2 cell loss, indicating complete self-sufficiency in maintaining NG2-glia population levels in the adult brain.

Spatiotemporally different origins of NG2 progenitors produce cortical interneurons versus glia in the mammalian forebrain

“…In postnatal CNS, oligodendrogliogenesis is a continuous process that requires the self-renewal activity of progenitors, namely, OPCs, in the form of active mitosis (17,18). However, in our analyses, most NG2 + cells in the dorsal CTX did not give rise to OLs, and thus did not qualify as classical OPCs.…”

Homeostasis of Microglia in the Adult Brain: Review of Novel Microglia Depletion Systems

“…This remains true for most of the CNS cell types, but some studies challenged this view by showing that many types of glial cells are able to self-maintain locally. Not only can oligodendrocyte progenitors establish their own homeostatic proliferation after depletion [67,68], but microglia can be stimulated to proliferate after pharmacological [10] or genetic [11] ablation. Both studies showed with immunohistological methods that the repopulating cells were BrdU + and Ki67 + .…”

NG2-Glia, a New Player in Energy Balance

“…They appear to sustain equidistance to one another through contact inhibition of their processes [10, 31]. When periventricular NG2-glia cells are ablated pharmacologically by exposure to the mitotic inhibitor cytosine-β-D-arabino­furanoside (AraC; see Box 1 for details on AraC-induced NG2-glia ablation), mice display a dramatic change in daily food intake, consuming up to twice as much chow as controls [32].…”

“…The principle confirmed function of NG2-glia is to act as a lifetime source of new oligodendrocytes, and it is well established that NG2-glia continue to proliferate throughout adulthood in both white and grey matter [8], including in the hypothalamus [10, 11]. In fact, NG2-glia are the most proliferative cells in the adult brain [12].…”

“…In fact, NG2-glia are the most proliferative cells in the adult brain [12]. They undergo self-renewing divisions [10, 13] as well as differentiating into myelinating oligodendrocytes [12, 14] and, by some accounts, neurons [11, 15-17]. NG2-glia-derived cells may serve to myelinate previously unmyelinated axons, remodel existing myelination, and repair the brain after demyelinating disease, holding the promise that a deeper understanding of NG2-glia biology could contribute to the effective treatment of degenerative disorders such as multiple sclerosis or traumatic brain injury [18-20].…”