HB-GAM (pleiotrophin) reverses inhibition of neural regeneration by the CNS extracellular matrix

Paveliev, Mikhail; Fenrich, Keith K.; Kislin, Mikhail; Kuja-Panula, Juha; Kulesskiy, Evgeny; Varjosalo, Markku; Kajander, Tommi; Mugantseva, Ekaterina; Ahonen-Bishopp, Anni; Khiroug, Leonard; Kulesskaya, Natalia; Rougon, Geneviève; Rauvala, Heikki

doi:10.1038/srep33916

Cited by 47 publications

(58 citation statements)

References 40 publications

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“…Recent work demonstrated the use of two-photon nanosurgery in the mouse brain to ablate single dendrites that resulted in rapid fragmentation of the distal end and formation of a retraction bulb ( Zhao et al , 2017 ). Using a prick-injury model in the cerebral cortex, another study showed dendritic regrowth by pyramidal cells after local injection of heparin-binding growth-associated molecule, an effect that was attributed to modification of the glial scar ( Paveliev et al , 2016 ). In our optic nerve injury model, RGC dendrites never regenerated unless they were stimulated with insulin, thus providing the first evidence of successful dendritic regeneration in retinal neurons.…”

Section: Discussionmentioning

confidence: 99%

Insulin signalling promotes dendrite and synapse regeneration and restores circuit function after axonal injury

Agostinone

Alarcón-Martínez

Gamlin

et al. 2018

Brain

102

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See Peterson and Benowitz (doi:) for a scientific commentary on this article.Dendrites retract and disconnect from their cellular partners in a number of psychiatric and neurodegenerative diseases. Agostinone et al. show that injured mammalian retinal ganglion cells have the capacity to regenerate dendrites and reestablish functional connections, and identify insulin signalling as paramount for a successful pro-regenerative response.

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Section: Discussionmentioning

confidence: 99%

Insulin signalling promotes dendrite and synapse regeneration and restores circuit function after axonal injury

Agostinone

Alarcón-Martínez

Gamlin

et al. 2018

Brain

102

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“…Use of the peptide delivered systemically following severe thoracic contusion resulted in remarkable functional recovery of the locomotor and urinary systems, possibly mediated, in part, through serotonergic sprouting and reinnervation caudal to the site of injury (221). Recently, Paveliev et al (304) have used the CS-binding protein pleiotrophin (a heparin-binding growth-associated molecule) to facilitate neural regeneration in vitro and in vivo. In preventing CS binding to PTP, they demonstrated increased sprouting following mild cortical and spinal cord injury, although this may additionally be linked to rapid reestablishment of the blood supply following trauma.…”

Section: Manipulating Chondroitin Sulfate-glycosaminoglycan Receptmentioning

confidence: 99%

The Biology of Regeneration Failure and Success After Spinal Cord Injury

Tran

Warren

Silver

2018

Physiological Reviews

619

557

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Since no approved therapies to restore mobility and sensation following spinal cord injury (SCI) currently exist, a better understanding of the cellular and molecular mechanisms following SCI that compromise regeneration or neuroplasticity is needed to develop new strategies to promote axonal regrowth and restore function. Physical trauma to the spinal cord results in vascular disruption that, in turn, causes blood-spinal cord barrier rupture leading to hemorrhage and ischemia, followed by rampant local cell death. As subsequent edema and inflammation occur, neuronal and glial necrosis and apoptosis spread well beyond the initial site of impact, ultimately resolving into a cavity surrounded by glial/fibrotic scarring. The glial scar, which stabilizes the spread of secondary injury, also acts as a chronic, physical, and chemo-entrapping barrier that prevents axonal regeneration. Understanding the formative events in glial scarring helps guide strategies towards the development of potential therapies to enhance axon regeneration and functional recovery at both acute and chronic stages following SCI. This review will also discuss the perineuronal net and how chondroitin sulfate proteoglycans (CSPGs) deposited in both the glial scar and net impede axonal outgrowth at the level of the growth cone. We will end the review with a summary of current CSPG-targeting strategies that help to foster axonal regeneration, neuroplasticity/sprouting, and functional recovery following SCI.

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“…Midkine [ 54 ] and pleiotrophin [ 55 ] partially overcome the inhibition of neurite growth by CSPGs, and improve axon regeneration in injury models of the spinal cord. Similar to its effects on neurons, pleiotrophin improved oligodendrocyte differentiation on aggrecan-coated substrates ( Fig 3B ), while its activity was markedly lower than that of PRM at the same concentrations ( Fig 3D ).…”

Section: Discussionmentioning

confidence: 99%

Protamine neutralizes chondroitin sulfate proteoglycan-mediated inhibition of oligodendrocyte differentiation

et al. 2017

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Chondroitin sulfate proteoglycans (CSPGs), which are enriched in demyelinating plaques in neurodegenerative diseases, such as multiple sclerosis (MS), impair remyelination by inhibiting the migration and differentiation of oligodendrocyte precursor cells (OPCs) in the central nervous system (CNS). We herein show that protamine (PRM, also known as a heparin antagonist) effectively neutralizes the inhibitory activities of CSPGs, thereby enhancing OPC differentiation and (re)myelination in mice. Cell-based assays using mouse OPC-like OL1 cells revealed that the PRM treatment exerted masking effects on extracellular CSPGs and improved oligodendrocyte differentiation on inhibitory CSPG-coated substrates. PRM also bound to the extracellular region of protein tyrosine phosphatase receptor type Z (PTPRZ), a membrane-spanning CSPG predominantly expressed in OPCs, and functioned as a ligand mimetic of PTPRZ, thereby suppressing its negative regulatory activity on oligodendrocyte differentiation. In primary cultures, the differentiation of OPCs from wild-type and Ptprz-deficient mice was equally enhanced by PRM. Moreover, the intranasal administration of PRM accelerated myelination in the developing mouse brain, and its intracerebroventricular administration stimulated remyelination after cuprizone-induced demyelination. These results indicate that PRM has CSPG-neutralizing activity which promotes oligodendrocyte differentiation under developmental and morbid conditions.

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HB-GAM (pleiotrophin) reverses inhibition of neural regeneration by the CNS extracellular matrix

Cited by 47 publications

References 40 publications

Insulin signalling promotes dendrite and synapse regeneration and restores circuit function after axonal injury

Insulin signalling promotes dendrite and synapse regeneration and restores circuit function after axonal injury

The Biology of Regeneration Failure and Success After Spinal Cord Injury

Protamine neutralizes chondroitin sulfate proteoglycan-mediated inhibition of oligodendrocyte differentiation

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