Astrocyte‐like subpopulation of NG2 glia in the adult mouse cortex exhibits characteristics of neural progenitor cells

Abstract

Glial cells expressing neuron‐glial antigen 2 (NG2), also known as oligodendrocyte progenitor cells (OPCs), play a critical role in maintaining brain health. However, their ability to differentiate after ischemic injury is poorly understood. The aim of this study was to investigate the properties and functions of NG2 glia in the ischemic brain. Using transgenic mice, we selectively labeled NG2‐expressing cells and their progeny in both healthy brain and after focal cerebral ischemia (FCI). Using single‐cell RNA sequencing, we classified the labeled glial cells into five distinct subpopulations based on their gene expression patterns. Additionally, we examined the membrane properties of these cells using the patch‐clamp technique. Of the identified subpopulations, three were identified as OPCs, whereas the fourth subpopulation had characteristics indicative of cells likely to develop into oligodendrocytes. The fifth subpopulation of NG2 glia showed astrocytic markers and had similarities to neural progenitor cells. Interestingly, this subpopulation was present in both healthy and post‐ischemic tissue; however, its gene expression profile changed after ischemia, with increased numbers of genes related to neurogenesis. Immunohistochemical analysis confirmed the temporal expression of neurogenic genes and showed an increased presence of NG2 cells positive for Purkinje cell protein‐4 at the periphery of the ischemic lesion 12 days after FCI, as well as NeuN‐positive NG2 cells 28 and 60 days after injury. These results suggest the potential development of neuron‐like cells arising from NG2 glia in the ischemic tissue. Our study provides insights into the plasticity of NG2 glia and their capacity for neurogenesis after stroke.

Nicotinic Acetylcholine Receptors in Glial Cells as Molecular Target for Parkinson’s Disease

“…Although it has been well established that neurons synapse on NG2 cells and have a modulatory role in their development and regeneration, very recently it was revealed that NG2 cells may themselves act as neural progenitor cells. This finding, which was reported in the cortex of adult mouse [245], if verified in human neuronal system, can have a wide implication in providing regenerative interventions in neurodegenerative diseases [245].…”

Nicotinic Acetylcholine Receptors in Glial Cells as Molecular Target for Parkinson’s Disease

“…Although it was well established that neurons synapse on NG2 cells and have a modulatory role in their development and regeneration, very recently, it was revealed that NG2 cells may themselves act as neural progenitor cells. This finding, which was reported in the cortex of adult mice [245], if verified in the human neuronal system, can have a wide implication in providing regenerative interventions for neurodegenerative diseases [245].…”

Directed differentiation of functional corticospinal-like neurons from endogenous SOX6+/NG2+ cortical progenitors

“…While some NG2-expressing progenitors generate oligodendrocytes throughout life, most of them do not differentiate, and remain proliferative in the cortex 68,130 . A subset of these cells generate protoplasmic astrocytes in the ventral forebrain and spinal cord 66,136 , and a smaller subset has been reported to generate neurons in the piriform cortex 137,138 and dorsolateral cortex 131 .…”

“…The broad group of cells often collectively characterized by shared expression of NG2 proteoglycan constitute ~2-3% of neural cells in adult rodent cortex, and are the primary proliferative cell group from early postnatal stages through adulthood and in the aged CNS 123,124 . Recent work reveals that this broad group of "NG2 progenitors" is not a homogeneous population; rather, it consists of at least several subpopulations with distinct molecular, cellular, and functional properties [125][126][127][128][129][130][131][132][133][134][135] . While some NG2-expressing progenitors generate oligodendrocytes throughout life, most of them do not differentiate, and remain proliferative in the cortex 68,130 .…”