Lysophosphatidic acid promotes the proliferation of adult Schwann cells isolated from axotomized sciatic nerve

We have previously found that adult Schwann cells express receptors for lysophosphatidic acid (EDG2, EDG7) and sphingosine-1-phosphate (EDG5) and that expression of these receptors is significantly upregulated in injured sciatic nerve coincident with postaxotomy Schwann cell proliferation. Based on these observations, we hypothesized that lysophosphatidic acid and/or sphingosine-l-phosphate promote Schwann cell mitogenesis in injured adult nerve. We found that both saturated and unsaturated forms of lysophosphatidic acid, but not sphingosine-l-phosphate, induce DNA synthesis in adult Schwann cells isolated from surgically transected sciatic nerve. Lysophosphatidic acid induces adult Schwann cell DNA synthesis in a dose-dependent manner, acting at 0.1- to 10-muM concentrations. Lysophosphatidic acid-mediated stimulation of adult Schwann cell DNA synthesis occurs via a signaling pathway involving a pertussis toxin-sensitive (G(i)/G(0)) G-protein. Activation of phosphatidylinositol-3-kinase, cAMP-dependent protein kinase A and mitogen-activated protein kinase kinase is also required for lysophosphatidic acid-induced Schwann cell mitogenesis. These findings demonstrate that lysophosphatidic acid promotes proliferation of adult Schwann cells isolated from injured nerve and are consistent with the hypothesis that lysophosphatidic acid promotes in vivo Schwann cell mitogenesis in regenerating peripheral nerve.