Erythropoietin promotes Schwann cell migration and assembly of the provisional extracellular matrix by recruiting β1 integrin to the cell surface

In peripheral nerve injury, Schwann cells undergo profound phenotypic modulation, adopting a migratory phenotype and remodeling the extracellular matrix so that it is permissive for axonal regrowth. Erythropoietin (Epo) and its receptor (EpoR) are expressed by Schwann cells after nerve injury, regulating inflammatory cytokine expression and minimizing the duration of neuropathic pain. The mechanism of Epo activity in the injured peripheral nerve remains incompletely understood. Herein, we demonstrate that Epo promotes Schwann cell migration in vitro on fibronectin (FN)-coated surfaces. Epo also rapidly recruits beta 1 integrin subunit to the Schwann cell surface by a JAK-2-dependent pathway. Although beta 1 integrin subunit-containing integrins were not principally responsible for Schwann cell adhesion or migration on FN under basal conditions, beta 1 gene-silencing blocked the ability of Epo to promote cell migration. Epo also induced Schwann cell FN expression in vitro and in. vivo. The FN was organized into insoluble fibrils by Epo-treated Schwann cells in vitro and into an extensive matrix surrounding Schwann cells in vivo. Our results support a model in which Epo promotes Schwann cell migration and assembly of the provisional extracellular matrix in the injured peripheral nerve by its effects on integrin recruitment to the cell surface and local FN production.