Neuronal RARβ Signaling Modulates PTEN Activity Directly in Neurons and via Exosome Transfer in Astrocytes to Prevent Glial Scar Formation and Induce Spinal Cord Regeneration

Goncalves, Maria B.; Malmqvist, Tony; Clarke, Earl E.; Hubens, Chantal J.; Grist, John; Hobbs, Carl; Trigo, Diogo; Risling, Mårten; Angéria, Maria; Damberg, Peter; Carlstedt, Thomas; Corcoran, Jonathan

doi:10.1523/jneurosci.1339-15.2015

Cited by 88 publications

(80 citation statements)

References 45 publications

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“…In a rat model of cervical dorsal root avulsion (C5–T1), the newly developed RARbeta agonist was given (23). After 4 weeks of treatment, behavioral tests showed recovery of sensory (the sticky tape test; sensing and removal) and locomotor function (the horizontal ladder test).…”

Section: Adjuvant Therapy For Spinal Cord Sensory Regenerationmentioning

confidence: 99%

New Treatments for Spinal Nerve Root Avulsion Injury

Carlstedt

2016

Front. Neurol.

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Further progress in the treatment of the longitudinal spinal cord injury has been made. In an inverted translational study, it has been demonstrated that return of sensory function can be achieved by bypassing the avulsed dorsal root ganglion neurons. Dendritic growth from spinal cord sensory neurons could replace dorsal root ganglion axons and re-establish a reflex arch. Another research avenue has led to the development of adjuvant therapy for regeneration following dorsal root to spinal cord implantation in root avulsion injury. A small, lipophilic molecule that can be given orally acts on the retinoic acid receptor system as an agonist. Upregulation of dorsal root ganglion regenerative ability and organization of glia reaction to injury were demonstrated in treated animals. The dual effect of this substance may open new avenues for the treatment of root avulsion and spinal cord injuries.

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Section: Adjuvant Therapy For Spinal Cord Sensory Regenerationmentioning

confidence: 99%

New Treatments for Spinal Nerve Root Avulsion Injury

Carlstedt

2016

Front. Neurol.

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“…In this regard, conflicting evidence exists over the importance of scar tissue as a barrier for axonal growth. A number of reports supporting the role of scar tissue as a barrier have shown that its removal facilitates neural restoration [16–18]. However, recent studies have also suggested that scar tissue is not necessarily an obstacle for regeneration and may even be necessary for neural restoration [19].…”

Section: Discussionmentioning

confidence: 99%

Immunization with neural derived peptides plus scar removal induces a permissive microenvironment, and improves locomotor recovery after chronic spinal cord injury

et al. 2017

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BackgroundImmunization with neural derived peptides (INDP) as well as scar removal—separately—have shown to induce morphological and functional improvement after spinal cord injury (SCI). In the present study, we compared the effect of INDP alone versus INDP with scar removal on motor recovery, regeneration-associated and cytokine gene expression, and axonal regeneration after chronic SCI. Scar removal was conducted through a single incision with a double-bladed scalpel along the stump, and scar renewal was halted by adding α,α′-dipyridyl.ResultsDuring the chronic injury stage, two experiments were undertaken. The first experiment was aimed at testing the therapeutic effect of INDP combined with scar removal. Sixty days after therapeutic intervention, the expression of genes encoding for TNFα, IFNγ, IL4, TGFβ, BDNF, IGF1, and GAP43 was evaluated at the site of injury. Tyrosine hydroxylase and 5-hydroxytryptamine positive fibers were also studied. Locomotor evaluations showed a significant recovery in the group treated with scar removal + INDP. Moreover; this group presented a significant increase in IL4, TGFβ, BDNF, IGF1, and GAP43 expression, but a decrease of TNFα and IFNγ. Also, the spinal cord of animals receiving both treatments presented a significant increase of serotonergic and catecholaminergic fibers as compared to other the groups. The second experiment compared the results of the combined approach versus INDP alone. Rats receiving INDP likewise showed improved motor recovery, although on a lesser scale than those who received the combined treatment. An increase in inflammation and regeneration-associated gene expression, as well as in the percentage of serotonergic and catecholaminergic fibers was observed in INDP-treated rats to a lesser degree than those in the combined therapy group.ConclusionsThese findings suggest that INDP, both alone and in combination with scar removal, could modify the non-permissive microenvironment prevailing at the chronic phase of SCI, providing the opportunity of improving motor recovery.

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“…Notably, exosomes released by neurons contain alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, while exosomes secreted from neurites of depolarized neurons are enriched with microtubuleassociated protein 1b (MAP1b) and miRNAs that target genes involved in neurite plasticity (86,87). Exosomes from neurons treated with a retinoic acid receptor β2 (RARβ) agonist had a dual effect on neurons and astrocytes to inactivate PTEN signaling, leading to enhancement of neurite outgrowth (88). RARβ agonist inactivated cortical neuron PTEN signaling by releasing exosomes enriched with PTEN.…”

Section: Exosomes and Neuronal Plasticitymentioning

confidence: 99%

“…RARβ agonist inactivated cortical neuron PTEN signaling by releasing exosomes enriched with PTEN. These PTEN-enriched neuronal exosomes transferred PTEN proteins into astrocytes to suppress astrocyte proliferation (88). In addition to neurons, exosomes released by cortical neurons transferred miR-124 to astrocytes and increased the expression of the excitatory amino acid transporter GLT-1 in astrocytes, suggesting a role for neuronal exosomes in regulatIn addition, activation of the Notch signaling pathway between cerebral endothelial cells and pericytes is required for cerebral angiogenesis and BBB integrity (72).…”

Section: Exosomes and Neuronal Plasticitymentioning

confidence: 99%