by Keyword: Nerve regeneration

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Hervera, A., Zhou, L., Palmisano, I., McLachlan, E., Kong, G., Hutson, T. H., Danzi, M. C., Lemmon, V. P., Bixby, J. L., Matamoros-Angles, A., Forsberg, K., De Virgiliis, F., Matheos, D. P., Kwapis, J., Wood, M. A., Puttagunta, R., del Río, J. A., Di Giovanni, S., (2019). PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure EMBO Journal 38, (13), e101032

The molecular mechanisms discriminating between regenerative failure and success remain elusive. While a regeneration-competent peripheral nerve injury mounts a regenerative gene expression response in bipolar dorsal root ganglia (DRG) sensory neurons, a regeneration-incompetent central spinal cord injury does not. This dichotomic response offers a unique opportunity to investigate the fundamental biological mechanisms underpinning regenerative ability. Following a pharmacological screen with small-molecule inhibitors targeting key epigenetic enzymes in DRG neurons, we identified HDAC3 signalling as a novel candidate brake to axonal regenerative growth. In vivo, we determined that only a regenerative peripheral but not a central spinal injury induces an increase in calcium, which activates protein phosphatase 4 that in turn dephosphorylates HDAC3, thus impairing its activity and enhancing histone acetylation. Bioinformatics analysis of ex vivo H3K9ac ChIPseq and RNAseq from DRG followed by promoter acetylation and protein expression studies implicated HDAC3 in the regulation of multiple regenerative pathways. Finally, genetic or pharmacological HDAC3 inhibition overcame regenerative failure of sensory axons following spinal cord injury. Together, these data indicate that PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure.

Keywords: Calcium, HDAC3, Nerve regeneration, Spinal cord injury, Transcription

Riggio, C., Nocentini, S., Catalayud, M. P., Goya, G. F., Cuschieri, A., Raffa, V., del Río, J. A., (2013). Generation of magnetized olfactory ensheathing cells for regenerative studies in the central and peripheral nervous tissue International Journal of Molecular Sciences 14, (6), 10852-10868

As olfactory receptor axons grow from the peripheral to the central nervous system (CNS) aided by olfactory ensheathing cells (OECs), the transplantation of OECs has been suggested as a plausible therapy for spinal cord lesions. The problem with this hypothesis is that OECs do not represent a single homogeneous entity, but, instead, a functionally heterogeneous population that exhibits a variety of responses, including adhesion and repulsion during cell-matrix interactions. Some studies report that the migratory properties of OECs are compromised by inhibitory molecules and potentiated by chemical gradients. In this paper, we report a system based on modified OECs carrying magnetic nanoparticles as a proof of concept experiment enabling specific studies aimed at exploring the potential of OECs in the treatment of spinal cord injuries. Our studies have confirmed that magnetized OECs (i) survive well without exhibiting stress-associated cellular responses; (ii) in vitro, their migration can be modulated by magnetic fields; and (iii) their transplantation in organotypic slices of spinal cord and peripheral nerve showed positive integration in the model. Altogether, these findings indicate the therapeutic potential of magnetized OECs for CNS injuries.

Keywords: Magnetic nanoparticle, Nerve regeneration, Olfactory ensheathing cell, Organotypic culture