Erythropoietin (EPO) Increases Myelin Gene Expression in CG4 Oligodendrocyte Cells through the Classical EPO Receptor

Abstract

Erythropoietin (EPO) has protective effects in neurodegenerative and neuroinflammatory diseases, including in animal models of multiple sclerosis, where EPO decreases disease severity. EPO also promotes neurogenesis and is protective in models of toxic demyelination. In this study, we asked whether EPO could promote neurorepair by also inducing remyelination. In addition, we investigated whether the effect of EPO could be mediated by the classical erythropoietic EPO receptor (EPOR), since it is still questioned if EPOR is functional in nonhematopoietic cells. Using CG4 cells, a line of rat oligodendrocyte precursor cells, we found that EPO increases the expression of myelin genes (myelin oligodendrocyte glycoprotein [MOG] and myelin basic protein [MBP]). EPO had no effect in wild-type CG4 cells, which do not express EPOR, whereas it increased MOG and MBP expression in cells engineered to overexpress EPOR (CG4-EPOR). This was reflected in a marked increase in MOG protein levels, as detected by Western blot. In these cells, EPO induced by 10-fold the early growth response gene 2 (Egr2), which is required for peripheral myelination. However, Egr2 silencing with a siRNA did not reverse the effect of EPO, indicating that EPO acts through other pathways. In conclusion, EPO induces the expression of myelin genes in oligodendrocytes and this effect requires the presence of EPOR. This study demonstrates that EPOR can mediate neuroreparative effects.

Erythropoietin accelerates functional recovery after moderate sciatic nerve crush injury

“…Schwann cells express a receptor for EPO, which may be responsible for the beneficial effects of EPO administration . EPO stimulates Schwann cell migration, and its administration has been shown to have a positive effect on myelination . These beneficial effects of EPO on myelination have already been translated into clinical trials for demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis .…”

Erythropoietin and a nonerythropoietic peptide analog promote aortic endothelial cell repair under hypoxic conditions: role of nitric oxide

“…RNA quality and concentration were determined using NanoDrop ND-1000 (NanoDrop Technologies, Thermo Fisher Scientific, Waltham, MA, USA) 20. Reverse transcription and real-time qPCR for EPOR, βCR, VEGF, and β2-microglobulin (a housekeeping gene not affected by changes in O 2 levels) were carried out on RNA samples using Taqman gene expression assays (Thermo Fisher Scientific) as previously reported 20,21. For gene expression quantification, the comparative threshold cycle (ΔΔCt) method was used following the guidelines of Thermo Fisher Scientific.…”

Peripheral nerve injury and myelination: Potential therapeutic strategies

“…Importantly, EPO‐mediated functional improvement can be demonstrated from single doses up to days after injuries in mice and seems to correlate with injury (Elfar et al, ). Although the mechanisms by which EPO works are still poorly understood, it is thought to work by promoting the expression of myelin genes, MPZ and PMP22 (Cervellini et al, ). We have shown that mice which received systemic EPO following nerve crush injury maintained more myelinated axons at the site of injury (Sundem et al, ).…”