The Differentiation of Rat Oligodendroglial Cells Is Highly Influenced by the Oxygen Tension: In Vitro Model Mimicking Physiologically Normoxic Conditions

Justyna Janowska,Malgorzata Ziemka-Nalecz,Joanna Sypecka

doi:10.3390/ijms19020331

Abstract

Oligodendrocyte progenitor cells (OPCs) constitute one of the main populations of dividing cells in the central nervous system (CNS). Physiologically, OPCs give rise to mature, myelinating oligodendrocytes and confer trophic support to their neighboring cells within the nervous tissue. OPCs are known to be extremely sensitive to the influence of exogenous clues which might affect their crucial biological processes, like survival, proliferation, differentiation, and the ability to generate a myelin membrane. Alterations in their differentiation influencing their final potential for myelinogenesis are usually the leading cause of CNS dys- and demyelination, contributing to the development of leukodystrophic disorders. The evaluation of the mechanisms that cause oligodendrocytes to malfunction requires detailed studies based on designed in vitro models. Since OPCs readily respond to changes in local homeostasis, it is crucial to establish restricted culture conditions to eliminate the potential stimuli that might influence oligodendrocyte biology. Additionally, the in vitro settings should mimic the physiological conditions to enable the obtained results to be translated to future preclinical studies. Therefore, the aim of our study was to investigate OPC differentiation in physiological normoxia (5% O2) and a restricted in vitro microenvironment. To evaluate the impact of the combined microenvironmental clues derived from other components of the nervous tissue, which are also influenced by the local oxygen concentration, the process of generating OPCs was additionally analyzed in organotypic hippocampal slices. The obtained results show that OPC differentiation, although significantly slowed down, proceeded correctly through its typical stages in the physiologically relevant conditions created in vitro. The established settings were also conducive to efficient cell proliferation, exerting also a neuroprotective effect by promoting the proliferation of neurons. In conclusion, the performed studies show how oxygen tension influences OPC proliferation, differentiation, and their ability to express myelin components, and should be taken into consideration while planning preclinical studies, e.g., to examine neurotoxic compounds or to test neuroprotective strategies.

Highlights

Oligodendrocyte progenitor cells (OPCs) are one of the major cell populations within the central nervous system (CNS)
After undergoing a multistage differentiation process orchestrated by a number of exogenous stimuli, they acquire the ability to myelinate axons within the CNS, assuring a fast and efficient signal propagation [3,4]
The myelinating oligodendrocytes supply neurons with metabolic substrates, like glycogen-derived pyruvate and lactate, via the monocarboxylate transporter 1, and enwrap axons with multilayered myelin sheaths to protect them from exogenous noxious stimuli [8,9,10]

Summary

Introduction

Oligodendrocyte progenitor cells (OPCs) are one of the major cell populations within the central nervous system (CNS). Apart from being the precursors of the mature myelinating oligodendrocytes, OPCs, which are recognized as neural/glial antigen 2 (NG2+) cells, are known to play additional roles in the nervous tissue. They confer a trophic support to their neighboring cells, stimulating neurogenesis and the differentiation of neurons by releasing neurotrophins (BDNF, NT-3), as well as exert an immunomodulatory effect in a pathophysiological environment [5,6,7]. The myelinating oligodendrocytes supply neurons with metabolic substrates, like glycogen-derived pyruvate and lactate, via the monocarboxylate transporter 1, and enwrap axons with multilayered myelin sheaths to protect them from exogenous noxious stimuli [8,9,10]

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