Satellite glial cells promote regenerative growth in sensory neurons

Abstract

Peripheral sensory neurons switch to a regenerative state after nerve injury to enable axon regeneration and functional recovery. Whether satellite glial cells (SGC), which completely surround the neuronal soma, contribute to the regenerative responses remains unexplored. Here we defined the transcriptional profile of SGC and identified Fabp7/BLBP as a novel marker of SGC. We report that nerve injury changes gene expression in SGC, which is mostly related to lipid metabolism, specifically fatty acid synthesis and PPARa signaling. Conditional deletion of Fatty acid synthase (Fasn), the committed enzyme in de novo fatty acid synthesis in SGC impairs axon regeneration. Treatment with the PPARa agonist fenofibrate rescues axon regeneration in mice lacking Fasn in SGC. This results indicates that PPARa functions downstream of fatty acid synthesis in SGC to promote axon regeneration. These results identify fatty acid synthesis in SGC as a fundamental novel mechanism mediating axon regeneration in adult peripheral nerves.

Ascending dorsal column sensory neurons respond to spinal cord injury and downregulate genes related to lipid metabolism

“…Our transcriptional profile analysis from whole DRG and FACS-sorted ascending DRG sensory neurons both suggested a potential role for downregulation of biosynthetic and lipid metabolic pathways after SCI in repressing axon regeneration. Decreased lipid metabolism after SCI in whole DRG is consistent with our recent observation that FASN expression in satellite glial cells promotes axon regeneration in peripheral nerves in part by activating PPARα in satellite glial cells 46 . Here we found that Fasn is also expressed in neurons, and is more significantly downregulated after SCI than SNI in ascending DRG sensory neurons.…”

“…Since adult DRG cultures include both neurons and nonneuronal cells, we cannot rule out the potential impact of FASN inhibition on non-neuronal cells in decreasing axon growth in vitro Indeed, neurite growth in culture hippocampal neurons was shown to be supported by phospholipid-loaded lipoproteins secreted from glial cells 45 . We also recently showed that FASN is required in satellite glial cells, which completely surround sensory neurons, to promote axon regeneration in peripheral nerves 46 . Therefore, to test if FASN is required intrinsically in neurons to promote axon growth, we used a spot culture assay, in which embryonic DRG are dissociated and cultured in a spot, allowing axons to extend radially from the spot 47,48 .…”

“…Therefore, to test if FASN is required intrinsically in neurons to promote axon growth, we used a spot culture assay, in which embryonic DRG are dissociated and cultured in a spot, allowing axons to extend radially from the spot 47,48 . By including the mitotic inhibitor 5-deoxyfluoruridine (FDU), we can obtain a culture enriched for neurons with limited amounts of other non-neuronal cell types 46 . The effects observed in these neuronal culture are thus largely intrinsic to sensory neurons.…”

Signals Orchestrating Peripheral Nerve Repair

“…Indeed, it has been reported that SC express distinct sensory and motor phenotypes and thus support regeneration in a phenotype-specific manner [156]. Additional contributors to the regeneration of sensory neurons are satellite glial cells (SGC), which completely envelop the neuronal soma: these cells allow close communication and molecular interchange and undergo injury-induced transcriptional changes, thereby forming a functional unit with the sensory neuron to orchestrate nerve repair [154,157].…”

More Than Mortar: Glia as Architects of Nervous System Development and Disease

“…Glial cells within the PNS and CNS are essential for proper guidance of axon and dendrite outgrowth (Mason and Sretavan, 1997;Poeck et al, 2001;Hidalgo, 2003;Chotard and Salecker, 2004;Chotard et al, 2005;Learte and Hidalgo, 2007;Procko and Shaham, 2010;Avraham et al, 2020;Rigby et al, 2020). This is required for directing information flow in local circuits and is also essential for broad nervous system organization.…”