Emerging Role of HDACs in Regeneration and Ageing in the Peripheral Nervous System: Repair Schwann Cells as Pivotal Targets

Abstract

The peripheral nervous system (PNS) has a remarkable regenerative capacity in comparison to the central nervous system (CNS), a phenomenon that is impaired during ageing. The ability of PNS axons to regenerate after injury is due to Schwann cells (SC) being reprogrammed into a repair phenotype called Repair Schwann cells. These repair SCs are crucial for supporting axonal growth after injury, myelin degradation in a process known as myelinophagy, neurotropic factor secretion, and axonal growth guidance through the formation of Büngner bands. After regeneration, repair SCs can remyelinate newly regenerated axons and support nonmyelinated axons. Increasing evidence points to an epigenetic component in the regulation of repair SC gene expression changes, which is necessary for SC reprogramming and regeneration. One of these epigenetic regulations is histone acetylation by histone acetyl transferases (HATs) or histone deacetylation by histone deacetylases (HDACs). In this review, we have focused particularly on three HDAC classes (I, II, and IV) that are Zn²⁺-dependent deacetylases. These HDACs are important in repair SC biology and remyelination after PNS injury. Another key aspect explored in this review is HDAC genetic compensation in SCs and novel HDAC inhibitors that are being studied to improve nerve regeneration.

Keywords: HDACs; HDACs therapies; Schwann cell; ageing; myelin; nerve injury; nerve regeneration; remyelination; repair Schwann cell.

Figure 1

Description of protein structure, localization, expression, and known biological functions of Zn²⁺ dependent HDACs [4,6,13,14,15,16,17]. (Dark grey rectangles containing an S indicate serine residues. Orange rectangles indicate a MEF2 binding site. Blue rectangles indicate the deacetylase domain. Yellow rectangle indicates a Zn²⁺ finger. White rectangle indicates leucine rich domain).

Figure 2

Hdac expression during mouse nerve development. Expression in transcripts per million (TPM). Graphs ggenerated based on RNA-seq data from Gerber et al., 2021, GEO database accession number GSE137870 [56]. Authors used four independent samples for bulk RNA sequencing at every time point, two from male and two from female mice. At E13.5 and E17.5, sciatic nerves were pooled from two embryos of the same sex per sample. At all postnatal time points examined (P1, P5, P14, P24, and P60), sciatic nerves from one mouse were used for each independent sample [56].

Figure 3

Hdac expression across different cells in the sciatic nerve at P1 (early developmental stage) and P60 (mouse adulthood). Data based on 10× genomics single cell RNA sequencing data from Gerber et al. (2021). Graphs generated based on RNA-seq data from Gerber et al., 2021 (GEO database accession number GSE137870). [56]. Three independent samples were included for each time point, processed as three independent 10× Genomics runs. Expression is detailed in proliferating (prol. SC), immature (iSC), and pro-myelinating (pmSC) Schwann cells; immune cells (IC), endothelial cells (EC), pericytes, and vascular smooth muscle cells (per/VMSC), pericytes/endothelial cells (Per/EC*), endothelial cells 1 and 2 (EC1&2), proliferating fibroblast-like cells (prol. Fb), fibroblast-related cells (FbRel*), endoneurial cells (EnC, also known as endoneurial fibroblasts or fibroblast-like cells), perineurial cells (PnC), and epineurial cells (EpC). Dot colour represents average expression level in cells expressing the Hdac of interest. Dot size represents percentage of cells expressing the Hdac of interest. (* indicates tentative label suggested by Gerber et al., 2021). Futher single cell RNA-seq gene expression can be checked in the Sciatic Nerves Atlas: https://snat.ethz.ch/index.html (Accessed on 26 February 2022).

Figure 4

Hdac expression in acute and chronic injury in young nerves or acute injury in aged nerves. (A) Hdac expression in young nerves, both in acute (up to 7 days) and chronic injury (up to 70 days). (B) Hdac expression in acute injury (3 days) in young and aged nerves. Expression in fragments per kilobase of exon per million mapped fragments (FPKM. Graphs generated based on RNA-seq data from Wagstaff et al., 2021 (ArrayExpress ID E-MTAB-9640) [87].