Is placental growth factor involved in spinal cord repair?

• ¹ University of Liege, GIGA Neurosciences, Belgium

Following axon injury, regeneration outcome depends on the central or peripheral localization of the lesion, thus on the environment through which the axon regrows. In the peripheral nervous system (PNS), the post-injury Wallerian degeneration (WD) inflammatory process occurs rapidly and involves mainly Schwann cells and monocyte-derived macrophages, leading to successful regeneration. In the central nervous system (CNS), WD that involves resident microglia and monocyte-derived macrophages is much slower, leading to a poor clearance of myelin debris and a hostile environment for the axon, whose regeneration is aborted. In this context, the cellular and molecular mechanisms regulating WD in the PNS and the CNS have been extensively studied. In particular, infiltration of monocyte-derived macrophages has been shown to be essential for recovery after spinal cord injury (SCI), but this recruitment needs to be well orchestrated. Among the molecules likely involved in this control, the Placental Growth Factor (PlGF) possesses various properties that could make it an interesting actor in the repair process. Indeed, PlGF is an angiogenic factor with neuroprotective and neurotrophic properties. Moreover, PlGF is able to attract and activate monocytes, and has recently been shown to be involved in macrophage M1/M2 polarization process. We thus decided to assess PlGF role in the molecular and cellular mechanisms that follow SCI. Using Pgf null mice (Pgf -/-), we compared their behavioural recovery to the one of their wild-type (WT) littermates after a thoracic spinal cord contusion injury. Quantification of lesion extension and immunohistological studies were performed on their respective spinal cord tissues. Surprisingly, behavioural data show that Pgf -/- mice recover their motor (BMS and BMS subscores) and sensory (Von Frey test) functions significantly better than wt mice. This is correlated to a significant decrease of the lesion volume in Pgf -/- mice (Luxol Fast Blue/Eosin staining), 28 days after SCI. However, no difference in axon regrowth was observed when assessed with Neurofilaments and Gap-43 immunostainings. We then examined the injured tissues 5 days after SCI, to compare the inflammatory response, and more particularly the M1/M2 macrophage polarity. We found that in the lesioned site of Pgf -/- mice, there is a significantly higher number of M2 – polarized macrophages than in wt mice. These original data, which will be further confirmed by RT-qPCR assays for pro- and anti-inflammatory cytokines, strongly suggest that in absence of PlGF, the lesion environment is an anti-inflammatory milieu, allowing tissue preservation and supporting recovery.