Lysophosphatidic Acid Promotes the Proliferation of Adult Schwann Cells Isolated from Axotomized Sciatic Nerve

Abstract

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-1-phosphate promote Schwann cell mitogenesis in injured adult nerve. We found that both saturated and unsaturated forms of lysophosphatidic acid, but not sphingosine-1-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-microM concentrations. Lysophosphatidic acid-mediated stimulation of adult Schwann cell DNA synthesis occurs via a signaling pathway involving a pertussis toxin-sensitive (G(i)/G(o)) 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.

Lysophosphatidic Acid Signaling in the Nervous System

“…In adult SCs isolated from axotomized sciatic nerve, Lpar1 and Lpar2 are coincidentally upregulated during post-axotomy SC proliferation, suggesting that LPA signaling promotes SC division in regenerating peripheral nerves (Weiner et al, 2001; Frohnert et al, 2003). In contrast, exogenous LPA induces demyelination of neurons in dorsal root ex vivo culture as well as in mice that have been intrathecally injected with LPA (Inoue et al, 2004).…”

Modulation of LPA Receptor Expression in the Human Brain Following Neurotrauma

“…LPA's involvement in neurogenesis is now well established (Kingsbury et al 2003); yet less is known of its role in the adult nervous system. In vitro experiments performed on adult mouse cells demonstrated that LPA induces neurite retraction of dorsal root ganglion neurons (Bouquet et al 2007) and stimulates proliferation, process retraction and motility of Schwann cells (Bouquet et al 2007;Frohnert et al 2003). Following CNS injury or ischemia, LPA-like activity increases within the CSF Tigyi et al 1995) and levels of ATX increase within astrocytes neighboring a lesion of the adult rat brain (Savaskan et al 2007), suggesting a role for LPA in brain injury responses.…”

LPA receptor expression in the central nervous system in health and following injury

“…Less is known of its role in the adult nervous system. In studies performed in vitro on adult mouse cells, LPA stimulates the proliferation, process retraction and motility of Schwann cells (Bouquet et al 2007;Frohnert et al 2003) and induces neurite retraction of dorsal root ganglion (DRG) neurons (Bouquet et al 2007). Following injury or ischemia of the nervous system, LPA-like activity increases within the cerebrospinal fluid thus, LPA concentrations probably increase within the CNS because of the impairment of the blood-brain barrier (Eichholtz et al 1993;Tigyi et al 1995).…”