Prostacyclin promotes oligodendrocyte precursor recruitment and remyelination after spinal cord demyelination

Abstract

Adult oligodendrocyte precursor cells (OPCs) are located adjacent to demyelinated lesion and contribute to myelin repair. The crucial step in remyelination is the migration of OPCs to the demyelinated area; however, the mechanism of OPC migration remains to be fully elucidated. Here we show that prostacyclin (prostaglandin I2, PGI2) promotes OPC migration, thereby promoting remyelination and functional recovery in mice after demyelination induced by injecting lysophosphatidylcholine (LPC) into the spinal cord. Prostacyclin analogs enhanced OPC migration via a protein kinase A (PKA)-dependent mechanism, and prostacyclin synthase expression was increased in the spinal cord after LPC injection. Notably, pharmacological inhibition of prostacyclin receptor (IP receptor) impaired remyelination and motor recovery, whereas the administration of a prostacyclin analog promoted remyelination and motor recovery after LPC injection. Our results suggest that prostacyclin could be a key molecule for facilitating the migration of OPCs that are essential for repairing demyelinated areas, and it may be useful in treating disorders characterized by demyelination.

Peripherally derived FGF21 promotes remyelination in the central nervous system

“…Spinal cord demyelination causes severe motor deficits, which recover in a time-dependent manner as a result of spontaneous remyelination (14,38). Therefore, we speculated that peripheral FGF21 is involved in improvement of motor function.…”

“…For example, plateletderived growth factor (PDGF) and basic fibroblast growth factor (FGF), which are expressed by astrocytes (10), are both important for OPC proliferation (12). Other studies have shown that factors secreted by vascular cells promote remyelination (13,14). Consistent with these findings, the CNS is isolated from the peripheral milieu by vascular barriers such as the blood-brain barrier (BBB) and blood-spinal cord barrier.…”

“…Furthermore, the MBP -demyelination area in the dorsal column of the spinal cord was larger in FGF21-KO mice than in control littermates ( Figure 4C). Under intact conditions, there was no significant difference between FGF21-KO mice and control liter (18) and myelin structures (14,25) with no change of neuronal number (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/JCI94337DS1). Histological analysis revealed the presence of extravasated cadaverine around the site of LPC injection 3 and 7 days after the operation ( Figure 1A).…”

The role of leptin in the central nervous system remyelination

“…OPC proliferation is enhanced by treatment with growth factors such as platelet-derived growth factor (PDGF) and basic fibroblast growth factor (FGF2) [20] . So far, the molecular mechanism of remyelination has been attributed to the factors produced by the CNS cells, such as astrocytes [21,22] , microglia [23,24] , and vasculature [25] , because the CNS is normally separated from the periphery in the presence of a vascular barrier (blood brain barrier [BBB], blood spinal cord barrier). However, several CNS regions (e.g.…”

“…To investigate whether the observation in vitro is consistent with in vivo remyelination, we used a lysophosphatidylcholine (LPC)-induced demyelination model mouse [35,36] , which also reveals spontaneous remyelination [25] . In this model, although we did not detect significant neuronal loss by the measurement of NeuN-positive cell number around the LPC injection site in the spinal cord, damage of the vascular barrier around the lesion site was found [37] .…”