Perineurial Glia Are Essential for Motor Axon Regrowth following Nerve Injury

Abstract

Development and maintenance of the peripheral nervous system (PNS) are essential for an organism to survive and reproduce, and damage to the PNS by disease or injury is often debilitating. Remarkably, the nerves of the PNS are capable of regenerating after trauma. However, full functional recovery after nerve injuries remains poor. Peripheral nerve regeneration has been studied extensively, with particular emphasis on elucidating the roles of Schwann cells and macrophages during degeneration and subsequent regeneration. In contrast, the roles of other essential nerve components, including perineurial glia, are poorly understood. Here, we use laser nerve transection and in vivo, time-lapse imaging in zebrafish to investigate the role and requirement of perineurial glia after nerve injury. We show that perineurial glia respond rapidly and dynamically to nerve transections by extending processes into injury sites and phagocytizing debris. Perineurial glia also bridge injury gaps before Schwann cells and axons, and we demonstrate that these bridges are essential for axon regrowth. Additionally, we show that perineurial glia and macrophages spatially coordinate early debris clearance and that perineurial glia require Schwann cells for their attraction to injury sites. This work highlights the complex nature of cell-cell interactions after injury and introduces perineurial glia as integral players in the regenerative process.

Schwann cells use TAM receptor-mediated phagocytosis in addition to autophagy to clear myelin in a mouse model of nerve injury

“…Indeed, our RNAseq transcriptomes indicate that Gas6, one of the bridging molecules required for TAM receptor function, is highly expressed by macrophages isolated from the injured peripheral nerve. Other possible compensatory mechanisms include activation of alternate Schwann cell pathways and increased clearance by yet other cell types such as perineurial cells (11). The redundancy of multiple cellular and molecular mechanisms to mediate myelin clearance in the injured peripheral nerve highlights the complexity of this process and its importance for successful nerve repair.…”

“…Accordingly, the abrogation of either of these pathways in macrophages leads to decreases in macrophage phagocytosis and delays in myelin clearance as well as impaired regeneration and functional recovery (7,10). Two types of tissueresident glial cells have also been recognized to contribute to myelin debris removal from the injured peripheral nerve: Schwann cells and perineurial cells (11)(12)(13). Despite recent progress toward a molecular understanding of the Schwann cell response to injury, our understanding of the Schwann cell-mediated mechanism of myelin removal has remained incomplete (14,15).…”

Glial Cell Plasticity During Development and Myelinopathies

“…The role of perineurial glia in response to injury had remained poorly understood until a recent paper identified this ensheathing glial cell population as an active responder essential for nerve regeneration following an axonal transection injury 2014). Using a laser transection assay in zebrafish, coupled with in vivo, time-lapse imaging, perineurial glia rapidly responded to nerve transections by extending membrane processes towards the injury site, phagocytizing debris and forming glial bridges that spanned the transection site allowing for axonal regrowth (Lewis & Kucenas, 2014 …”

“…In both fish and mouse, perineurial glia are required for motor axon pathfinding from the spinal cord, restricting ectopic migration of motor neuron cell bodies into the periphery and are necessary for Schwann cell development and peripheral myelination (Binari et al, 2013;Clark et al, 2014;Kucenas et al, 2008b). Additionally, we recently discovered perineurial glia are essential mediators of nerve regeneration by phagocytizing debris and forming glial bridges across injury sites (Lewis & Kucenas, 2014). Although we have begun to reveal the importance of perineurial glia in development, we still lack an understanding of how they respond in disease states, like peripheral myelinopathies.…”

“…Following peripheral myelin perturbations in zebrafish, mice and humans, oligodendrocytes are found ectopically along spinal motor root axons (Coulpier et al, 2010;Kucenas et al, 2009;Lewis & Kucenas, 2014;Smith et al, 2014;Weinberg et al, 1975 OPCs. However, the functionality of the perineurium fails, further supporting the importance of Schwann cell-perineurial glial interactions during spinal motor nerve development and maintenance Sharghi-Namini et al, 2006).…”