The cortical NG2-glia response to traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a significant worldwide cause of morbidity and mortality. A chronic neurologic disease bearing the moniker of "the silent epidemic," TBI currently has no targeted therapies to ameliorate cellular loss or enhance functional recovery. Compared with those of astrocytes, microglia, and peripheral immune cells, the functions and mechanisms of NG2-glia following TBI are far less understood, despite NG2-glia comprising the largest population of regenerative cells in the mature cortex. Here, we synthesize the results from multiple rodent models of TBI, with a focus on cortical NG2-glia proliferation and lineage potential, and propose future avenues for glia researchers to address this unique cell type in TBI. As the molecular mechanisms that regulate NG2-glia regenerative potential are uncovered, we posit that future therapeutic strategies may exploit cortical NG2-glia to augment local cellular recovery following TBI.

Keywords: NG2-glia; oligodendrocyte precursor cells; traumatic brain injury.

Figure 1.. Models of Rodent TBI.

(A) In the stab wound injury (SWI) model, a sharp blade or needle is precisely inserted through a surgically created craniotomy into cortex (or cerebellum) and withdrawn. While the injury is dependent on the size and depth of the blade, this is most often a focal, mild TBI. (B) In “open head” injury models (e.g. controlled cortical impact, weight drop, fluid percussion injury), a mechanical force is directly applied to the brain parenchyma through a surgically created craniotomy. (C) In “closed head” injury models, the mechanical force is applied to the skull, either with or without a scalp incision. While more closely resembling clinical TBI, this model more often provides more heterogenous injuries than the open model (B). (D) Rotational acceleration injury models do not direct force towards the brain/skull, rather, rotate the brain relative to the skull around a fixed axis. Some models require a mount affixed directly to the skull, while others are capable of rotation of a freely mobile head. The result is tissue shear and axonal injury, with minimal direct contusional pathology. Created with BioRender.com

Figure 2.. Molecular pathways controlling cortical NG2-glia proliferation and differentiation.

Cortical NG2-glia respond to neurotrauma with robust proliferation and differentiation. (A) Reactive NG2-glia (green) polarize and migrate towards the site of TBI, while NG2-glia remote from the injury (magenta) lack any apparent morphologic changes. (B) In the acute response to TBI, reactive cortical NG2-glia (green) most commonly proliferate, leading to additional NG2-glia (large black arrow). A smaller population of NG2-glia undergo differentiation to mature oligodendrocytes (small black arrow). While data from stab wound injury models suggest that only few NG2-glia may be able to differentiate into Type 2 astrocytes or “astrocyte-like NG2-glia” (gray arrow), it is possible that larger lesions with ischemia or more significant blood brain barrier compromise may promote an astrocytic lineage potential through activation of BMP signaling (e.g. fibrinogen). Although NG2-glia have not been observed to differentiate into neurons under physiologic conditions in vivo (yellow arrow), virus-mediated expression of specific transcription factors (e.g. Sox2, NeuroD1) may be able to induce such a fate following TBI. Created with BioRender.com