Oligodendrocyte precursor cells: the multitaskers in the brain

Abstract

In the central nervous system, oligodendrocyte precursor cells (OPCs) are recognized as the progenitors responsible for the generation of oligodendrocytes, which play a critical role in myelination. Extensive research has shed light on the mechanisms underlying OPC proliferation and differentiation into mature myelin-forming oligodendrocytes. However, recent advances in the field have revealed that OPCs have multiple functions beyond their role as progenitors, exerting control over neural circuits and brain function through distinct pathways. This review aims to provide a comprehensive understanding of OPCs by first introducing their well-established features. Subsequently, we delve into the emerging roles of OPCs in modulating brain function in both healthy and diseased states. Unraveling the cellular and molecular mechanisms by which OPCs influence brain function holds great promise for identifying novel therapeutic targets for central nervous system diseases.

Keywords: Blood-brain barrier; Immunomodulator; Neural circuits; Neuron-OPC interaction; OPC; Oligodendrocyte precursor cells.

Fig. 1

Integration of OPCs into neural circuits occurs through multiple pathways. A OPCs receive glutamatergic signals via AMPA and NMDA receptors, as well as GABAergic input through GABA_A and GABA_B receptors expressed on their postsynaptic membrane. B OPCs regulate neuronal density, activity, and synaptic plasticity by releasing TNF-related weak inducer of apoptosis (TWEAK), fibroblast growth factor 2 (FGF2), and prostaglandin D2 synthase (PTGDS), and cleaved ectodomain of NG2 protein. C OPCs sense neuronal activity through the potassium channel Kir4.1. Upon axonal stimulation, Kir4.1 mediates an increase in intracellular potassium concentration in OPCs, potentially contributing to the maintenance of extracellular potassium homeostasis. D In the juvenile brain, OPCs phagocytose axons and excitatory presynapses, thus mediating neural network activity. E The interaction of OPCs with components of the neural vascular unit, including endothelial cells, pericytes, and astroglial endfeet, is crucial for maintaining the integrity of blood-brain barrier. For example, OPCs release hypoxia-inducible factor (HIF) to promote angiogenesis and tumor growth factor β (TGFβ) to increase tight junction protein (TJP) expression and subsequent BBB integrity. F OPCs modulate microglia activity and immune response by releasing TGFβ, which acts on the TGFβ receptor (TGFβR) of microglia. Activation of TGFβR may upregulate proteins such as CX3CR1, CSF1R, P2Y12R, and TMEM119, since knockdown of TGFβR in microglia led to downregulation of these proteins. G OPCs also recruit T cells by releasing chemokines, such as C-C motif ligand 2 (CCL2), CCL5, and CXCL10. The expression of major histocompatibility complex I and II (MHC-I/II) by OPCs activates T cells, while the expression of programmed death ligands (PD-L) suppresses T cell activity. Furthermore, OPCs can induce T cell apoptosis through Fas ligand (FasL). (created with BioRender.com)