Abstract
Oligodendrocytes, which are the main cell type in cerebral white matter, are generated from their precursor cells (oligodendrocyte precursor cells: OPCs). However, the differentiation from OPCs to oligodendrocytes is disturbed under stressed conditions. Therefore, drugs that can improve oligodendrocyte regeneration may be effective for white matter-related diseases. Here we show that a vasoactive peptide adrenomedullin (AM) promotes the in vitro differentiation of OPCs under pathological conditions. Primary OPCs were prepared from neonatal rat brains, and differentiated into myelin-basic-protein expressing oligodendrocytes over time. This in vitro OPC differentiation was inhibited by prolonged chemical hypoxic stress induced by non-lethal CoCl2 treatment. However, AM promoted the OPC differentiation under the hypoxic stress conditions, and the AM receptor antagonist AM22–52 canceled the AM-induced OPC differentiation. In addition, AM treatment increased the phosphorylation level of Akt in OPC cultures, and correspondingly, the PI3K/Akt inhibitor LY294002 blocked the AM-induced OPC differentiation. Taken together, AM treatment rescued OPC maturation under pathological conditions via an AM-receptor-PI3K/Akt pathway. Oligodendrocytes play critical roles in white matter by forming myelin sheath. Therefore, AM signaling may be a promising therapeutic target to boost oligodendrocyte regeneration in CNS disorders.
Highlights
Oligodendrocytes are one of the major cell types in the cerebral white matters
When oligodendrocyte precursor cells (OPCs) were maintained in differentiation media (e.g. Dulbecco’s Modified Eagle’s Medium (DMEM) plus 2% B27 including 10 ng/ml CNTF, 15 nM T3 over 7 days), the cells began to exhibit oligodendrocyte-like phenotypes with myelin-basic-protein (MBP) expression (Figure 1A: control group)
OPC differentiation was suppressed by prolonged hypoxia induced by non-lethal CoCl2 treatment for 7 days [28, 29] (Figure 1A: CoCl2-treated group)
Summary
Oligodendrocytes are one of the major cell types in the cerebral white matters. They produce a lipid-rich membrane called myelin, which enwrap up to 60 axonal segments each (i.e. myelin sheath). Some OPCs may persist in an immature state. These residual OPCs are widely distributed in adult brains, comprising 5– 8% of all cells [2]. Myelinated tracts are formed early in life, renewal of myelin and oligodendrocyte continues throughout most of the adult life [3,4,5]. Residual OPCs may play an important part in these endogenous mechanisms of white matter repair and renewal
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