Involvement of placental growth factor in Wallerian degeneration

Abstract

Wallerian degeneration (WD) is an inflammatory process of nerve degeneration, which occurs more rapidly in the peripheral nervous system compared with the central nervous system, resulting, respectively in successful and aborted axon regeneration. In the peripheral nervous system, Schwann cells (SCs) and macrophages, under the control of a network of cytokines and chemokines, represent the main cell types involved in this process. Within this network, the role of placental growth factor (PlGF) remains totally unknown. However, properties like monocyte activation/attraction, ability to increase expression of pro-inflammatory molecules, as well as neuroprotective effects, make it a candidate likely implicated in this process. Also, nothing is described about the expression and localization of this molecule in the peripheral nervous system. To address these original questions, we decided to study PlGF expression under physiological and degenerative conditions and to explore its role in WD, using a model of sciatic nerve transection in wild-type and Pgf(-/-) mice. Our data show dynamic changes of PlGF expression, from periaxonal in normal nerve to SCs 24h postinjury, in parallel with a p65/NF-κB recruitment on Pgf promoter. After injury, SC proliferation is reduced by 30% in absence of PlGF. Macrophage invasion is significantly delayed in Pgf(-/-) mice compared with wild-type mice, which results in worse functional recovery. MCP-1 and proMMP-9 exhibit a 3-fold reduction of their relative expressions in Pgf(-/-) injured nerves, as demonstrated by cytokine array. In conclusion, this work originally describes PlGF as a novel member of the cytokine network of WD.

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

“…It also promotes survival of cortical neurons (Du et al 2010), promotes axon growth cone formation of dorsal root ganglion neurons , and stimulates proliferation and migration of Schwann cells (Chaballe et al 2011a). PlGF enhances growth of tumor cells, both of solid and hematological tumors (Fischer et al 2008;Schmidt et al 2011).…”

“…How these differential effects of PlGF in particular cell types regulate the overall outcome of cerebral ischemia remains to be further unraveled. In the peripheral nervous system, PlGF is detectable in axons of the sciatic nerve, and in Schwann cells after axotomy (Chaballe et al 2011a). Knockout studies indicate that PlGF stimulates proliferation and migration of Schwann cells and promotes an inflammatory response by recruiting macrophages via up-regulation of MCP-1, essential for axonal regeneration (Chaballe et al 2011a).…”

“…In the peripheral nervous system, PlGF is detectable in axons of the sciatic nerve, and in Schwann cells after axotomy (Chaballe et al 2011a). Knockout studies indicate that PlGF stimulates proliferation and migration of Schwann cells and promotes an inflammatory response by recruiting macrophages via up-regulation of MCP-1, essential for axonal regeneration (Chaballe et al 2011a). PlGF also antagonizes chemo-repulsive effects of Sema3A on dorsal root ganglion neurons through NRP binding ).…”

Peripheral Nerve Regeneration by Secretomes of Stem Cells from Human Exfoliated Deciduous Teeth

“…Macrophages, a phenotypically diverse population of immune cells, are integrated into both nerve degeneration and regeneration [8][9][10]. Macrophages reach the injury site within 24 h and reach a peak number within 2-3 days [11,12].…”

Schwann Cell Metabolic Activity in Various Short-Term Holding Conditions: Implications for Improved Nerve Graft Viability

“…Moreover, functional nerve regeneration requires not only axonal sprouting and elongation, but also remyelination and appropriate ion channel deployment at the node of Ranvier [8, 9]. The combination of surgical nerve repair and transplantation of peripheral myelin-forming cells has been shown to enhance axonal regeneration and remyelinate demyelinated fibers in experimental models [10] and is currently being investigated in clinical studies [7, 11]. …”