Inhibition of Astrocyte Connexin 43 Channels Facilitates the Differentiation of Oligodendrocyte Precursor Cells Under Hypoxic Conditions In Vitro

Qiong Wang,Yeye Tian,Zhiyuan Yu,Fengfei Ding,Huaqiu Zhang,Minjie Xie,Zhen Wang,Yongkang Fang,Wei Wang

doi:10.1007/s12031-018-1061-y

Abstract

Oligodendrocyte precursor cells (OPCs) proliferation and differentiation are essential for remyelination after white matter injury. Astrocytes could promote oligodendrogenesis after white matter damage whereas the underlying mechanisms are unknown. In this study, the role of astrocytic connexin43 (Cx43) hemichannels involved in OPC proliferation and differentiation in chronic hypoxia was evaluated. In an astrocyte-OPC co-culture chronic hypoxia model, OPCs became proliferative but failed to mature into oligodendrocytes. Application of astrocytic Cx43 blockers attenuated astrocyte activation, suppressed Cx43 hemichannel uptake activity and glutamate release induced by hypoxia, as well as improved OPC differentiation. Moreover, AMPA but not NMDA glutamate receptor antagonist rescued OPC differentiation in hypoxia. In conclusion, these findings suggested that astrocytic Cx43 hemichannel inhibition could potentially improve OPC maturation by attenuating AMPAR-mediated glutamate signaling. Astrocytic Cx43 hemichannels could serve as a potential therapeutic target for remyelination after chronic hypoxia.

Highlights

Oligodendrocyte precursor cells (OPCs) are immature forms of oligodendrocytes (OLs) and play essential roles in remyelination after white matter injury
We showed that inhibition of astrocytic Cx43 could suppress glutamate release via hemichannels and promote OPC maturation after chronic hypoxia injury via amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition
AMPA receptor but not NMDA receptor antagonist partially enhanced the maturation of OPCs under hypoxia

Summary

Introduction

Oligodendrocyte precursor cells (OPCs) are immature forms of oligodendrocytes (OLs) and play essential roles in remyelination after white matter injury. Astrocytic Cx43 has been shown required for OPC proliferation and differentiation, which is critical for myelin maintenance (Niu et al 2016; Orthmann-Murphy et al 2008; Tress et al 2012). Deletion of astrocytic Cx43 inhibited OPC proliferation (Niu et al 2016) while Cx43/Cx32 double-knockout mice developed white matter damage at early age (Tress et al 2012). Our previous study showed that knockout of astrocytic Cx43 significantly attenuated neuronal loss in MCAO models (Xie et al 2011). It has not been studied if inhibiting astrocytic Cx43 is protective for myelin maintanence and

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Conclusion