Oligodendrocyte Progenitor Cells Directly Utilize Lactate for Promoting Cell Cycling and Differentiation

Abstract

Oligodendrocyte progenitor cells (OPCs) undergo marked morphological changes to become mature oligodendrocytes, but the metabolic resources for this process have not been fully elucidated. Although lactate, a metabolic derivative of glycogen, has been reported to be consumed in oligodendrocytes as a metabolite, and to ameliorate hypomyelination induced by low glucose conditions, it is not clear about the direct contribution of lactate to cell cycling and differentiation of OPCs, and the source of lactate for remyelination. Therefore, we evaluated the effect of 1,4‐dideoxy‐1,4‐imino‐d‐arabinitol (DAB), an inhibitor of the glycogen catabolic enzyme glycogen phosphorylase, in a mouse cuprizone model. Cuprizone induced demyelination in the corpus callosum and remyelination occurred after cuprizone treatment ceased. This remyelination was inhibited by the administration of DAB. To further examine whether lactate affects proliferation or differentiation of OPCs, we cultured mouse primary OPC‐rich cells and analyzed the effect of lactate. Lactate rescued the slowed cell cycling induced by 0.4 mM glucose, as assessed by the BrdU‐positive cell ratio. Lactate also promoted OPC differentiation detected by monitoring the mature oligodendrocyte marker myelin basic protein, in the presence of both 36.6 mM and 0.4 mM glucose. Furthermore, these lactate‐mediated effects were suppressed by the reported monocarboxylate transporter inhibitor, α‐cyano‐4‐hydroxy‐cinnamate. These results suggest that lactate directly promotes the cell cycling rate and differentiation of OPCs, and that glycogen, one of the sources of lactate, contributes to remyelination in vivo. J. Cell. Physiol. 232: 986–995, 2017. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

Differential effects of glucose deprivation on the survival of fetal versus adult neural stem cells‐derived oligodendrocyte precursor cells

“…Notably, OGD alters the gene expression profile in adult cultures only, increasing the expression level of genes involved in glycolysis, the regulation of glucose metabolism, the TCA cycle, PPP, glycogen synthesis, glycogen degradation, and glycogen metabolism. This gene expression regulation indicates that adult OPCs/astrocytes mixed cultures exposed to OGDs are able to regulate glycolysis, as was expected, but that they also fuel production from alternative substrates, such as glycogen, necessary for OPC survival and differentiation (Ichihara et al, ).…”

“…OGDs are able to regulate glycolysis, as was expected, but that they also fuel production from alternative substrates, such as glycogen, necessary for OPC survival and differentiation (Ichihara et al, 2017).…”

Monocarboxylate transporter 1 and the vulnerability of oligodendrocyte lineage cells to metabolic stresses

“…Glycogen is highly enriched in white matter such as the corpus callosum where astrocyte density is high . Meanwhile, studies on glycogen phosphorylase inhibitor—DAB showed that, by inhibiting the hydrolysis of glycogen, DAB suppresses lactate release and worsens the outcome in myelin remodeling . Therefore, the role of lactate in response to metabolic demand is critical.…”

Glia-neuron energy metabolism in health and diseases: New insights into the role of nervous system metabolic transporters

“…Our lab, and others, have previously reported higher expression of MCT1 in the CNS myelin than in axons and conversely higher expression of MCT2 in axons than myelin (Rinholm et al, 2011) (Lee et al, 2012). Recent studies have also identified that oligodendrocyte progenitor cells (OPCs) utilize lactate through MCTs and that lactate, produced from glycogen, is crucial to promote cell cycling and differentiation in OPC-rich culture (Ichihara et al, 2017). Surprisingly, an in vitro study using co-cultures of DRG neurons and Schwann cells demonstrated increased myelination following downregulation of MCT1 in Schwann cells by lentiviral shRNAs (Domenech-Estevez et al, 2015); thus the exact role of this transporter in SC myelination in not yet clear.…”