Chondroitinase improves anatomical and functional outcomes after primate spinal cord injury

Rosenzweig, E; Salegio, Ernesto A.; Liang, Justine H; Weber, Janet L.; Weinholtz, Chase A.; Brock, J. H.; Moseanko, Rod; Hawbecker, Stephanie; Pender, Roger; Cruzen, Christina; Iaci, Jennifer F.; Caggiano, Anthony O.; Blight, Andrew R.; Haenzi, Barbara; Huie, J. Russell; Havton, Leif A.; Nout‐Lomas, Yvette S.; Fawcett, James W.; Ferguson, Adam R.; Beattie, Michael S.; Bresnahan, Jacqueline C.; Tuszynski, Mark H.

doi:10.1038/s41593-019-0424-1

Cited by 106 publications

(73 citation statements)

References 59 publications

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“…For example, astrocytes react and form a dense barrier around the lesion, stromal cells invade and form fibrous connective tissue with dense collagen and CSPG deposition, and OPCs proliferate and surround dystrophic axons (Pasterkamp and Verhaagen, 2006;Cregg et al, 2014;Dias et al, 2018). Efforts to prevent or dissociate the glial scar have been shown to improve axon regeneration (for example, see Rosenzweig et al, 2019). However, the biology of the glial scar is much more nuanced, and oversimplification of this complex healing and regeneration process can hinder advances in the field (Bradbury and Burnside, 2019).…”

Section: Modulating Glial Cell-axonal Growth Cone Interactions To Aidmentioning

confidence: 99%

Glial Cell-Axonal Growth Cone Interactions in Neurodevelopment and Regeneration

2020

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The developing nervous system is a complex yet organized system of neurons, glial support cells, and extracellular matrix that arranges into an elegant, highly structured network. The extracellular and intracellular events that guide axons to their target locations have been well characterized in many regions of the developing nervous system. However, despite extensive work, we have a poor understanding of how axonal growth cones interact with surrounding glial cells to regulate network assembly. Gliato-growth cone communication is either direct through cellular contacts or indirect through modulation of the local microenvironment via the secretion of factors or signaling molecules. Microglia, oligodendrocytes, astrocytes, Schwann cells, neural progenitor cells, and olfactory ensheathing cells have all been demonstrated to directly impact axon growth and guidance. Expanding our understanding of how different glial cell types directly interact with growing axons throughout neurodevelopment will inform basic and clinical neuroscientists. For example, identifying the key cellular players beyond the axonal growth cone itself may provide translational clues to develop therapeutic interventions to modulate neuron growth during development or regeneration following injury. This review will provide an overview of the current knowledge about glial involvement in development of the nervous system, specifically focusing on how glia directly interact with growing and maturing axons to influence neuronal connectivity. This focus will be applied to the clinically-relevant field of regeneration following spinal cord injury, highlighting how a better understanding of the roles of glia in neurodevelopment can inform strategies to improve axon regeneration after injury.

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Section: Modulating Glial Cell-axonal Growth Cone Interactions To Aidmentioning

confidence: 99%

Glial Cell-Axonal Growth Cone Interactions in Neurodevelopment and Regeneration

2020

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“…While average group differences are small, 10% of the treated dogs recovered independent ambulation which may represent an estimate of the “true” population effect is in such a large and heterogeneous sample size of 60 dogs (Moon & Bradbury, ). Cervical hemisection in rhesus monkeys and intrathecal administration 4 weeks later resulted in increased CST axon growth and formation of synapses from CST axons caudal to the lesion (Rosenzweig et al, ). This correlated with improved hand function compared to vehicle‐treated controls.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic repair for spinal cord injury: combinatory approaches to address a multifaceted problem

2020

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The recent years saw the advent of promising preclinical strategies that combat the devastating effects of a spinal cord injury (SCI) that are progressing towards clinical trials. However, individually, these treatments produce only modest levels of recovery in animal models of SCI that could hamper their implementation into therapeutic strategies in spinal cord injured humans. Combinational strategies have demonstrated greater beneficial outcomes than their individual components alone by addressing multiple aspects of SCI pathology. Clinical trial designs in the future will eventually also need to align with this notion. The scenario will become increasingly complex as this happens and conversations between basic researchers and clinicians are required to ensure accurate study designs and functional readouts.

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“…PNNs have been implicated in regulating plasticity within CNS tissue (Sorg et al, 2016;Fawcett et al, 2019), and their digestion using the chondroitinase ABC enzyme (within the intermediate zone and ventral horn) has been linked to improved functional recovery following spinal injury (Rosenzweig et al, 2019). As illustrated in our monkeys (Figure 8)…”

Section: Perineuronal Nets Were Not Implicated In Axonal Sprouting Inmentioning

confidence: 75%

Reorganization of the Primate Dorsal Horn in Response to a Deafferentation Lesion Affecting Hand Function

Fisher

Garner

Darian‐Smith

2019

Preprint

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The loss of sensory input following a spinal deafferentation injury can be debilitating, and this is especially true in primates when the hand is involved. While significant recovery of function occurs, little is currently understood about the reorganization of the neuronal circuitry, particularly within the dorsal horn. This region receives primary afferent input from the periphery, and cortical input via the somatosensory subcomponent of the corticospinal tract (S1 CST), and is critically important in modulating sensory transmission, both in normal and lesioned states. To determine how dorsal horn circuitry alters to facilitate recovery post-injury, we used an established deafferentation lesion (DRL/DCL -dorsal root/dorsal column) model in monkeys to remove sensory input from just the opposing digits (D1-D3) of one hand. This results in a deficit in fine dexterity that then recovers over several months. Electrophysiological mapping, tract tracing, and immunolabeling techniques were combined to delineate specific changes to dorsal horn input circuitry. Our main findings show that (1) there is complementary sprouting of the primary afferent and S1 CST populations into an overlapping region of the reorganizing dorsal horn, (2) afferent and efferent inputs converge on neuronal cell bodies in the dorsal horn pre-and post-injury, though most inputs are likely to be axodendritic, and (3) there is a loss of larger S1 CST terminal boutons in the affected dorsal horn, but no change in the size profile of the spared/sprouted primary afferent terminal boutons post-lesion.Understanding such changes helps to inform new and targeted therapies that best promote recovery. Significance statementSpinal injuries that remove sensation from the hand, can be debilitating, though functional recovery does occur. We examined changes to the neuronal circuitry of the dorsal horn in monkeys following a lesion that deafferented three digits of one hand. Little is understood about dorsal horn circuitry, despite the fact that this region loses most of its normal input after such an injury, and is clearly a major focus of reorganization. We found that both the spared primary afferents and somatosensory corticospinal efferents sprouted in an overlapping region of the dorsal horn after injury, and that larger (presumably faster) corticospinal terminals are lost, suggesting a significantly altered cortical modulation of primary afferents. Understanding this changing circuitry is important for designing targeted therapies.

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Chondroitinase improves anatomical and functional outcomes after primate spinal cord injury

Cited by 106 publications

References 59 publications

Glial Cell-Axonal Growth Cone Interactions in Neurodevelopment and Regeneration

Glial Cell-Axonal Growth Cone Interactions in Neurodevelopment and Regeneration

Therapeutic repair for spinal cord injury: combinatory approaches to address a multifaceted problem

Reorganization of the Primate Dorsal Horn in Response to a Deafferentation Lesion Affecting Hand Function

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