Jul 20, 2019 Last Updated 10:53 AM, Jul 6, 2019

Spinal cord injury

Human Mesenchymal Stromal Cell-Derived Extracellular Vesicles Modify Microglial Response and Improve Clinical Outcomes in Experimental Spinal Cord Injury

Ruppert KA, Nguyen TT, Prabhakara KS, Toledano Furman NE, Srivastava AK, Harting MT, Cox CS Jr. & Olson SD

Science Reports - Jan 2018


No current clinical intervention can alter the course of acute spinal cord injury (SCI), or appreciably improve neurological outcome. Mesenchymal stromal cells (MSCs) have been shown to modulate the injury sequelae of SCI largely via paracrine efects, although the mechanisms remain incompletely understood. One potential modality is through secretion of extracellular vesicles (EVs). In this study, we investigate whether systemic administration of EVs isolated from human MSCs (MSCEv) has the potential to be efcacious as an alternative to cell-based therapy for SCI. Additionally, we investigate whether EVs isolated from human MSCs stimulated with pro-infammatory cytokines have enhanced anti-infammatory efects when administered after SCI. Immunohistochemistry supported the quantitative analysis, demonstrating a diminished infammatory response with apparent astrocyte and microglia disorganization in cord tissue up to 10mm caudal to the injury site. Locomotor recovery scores showed signifcant improvement among animals treated with MSCEv. Signifcant increases in mechanical sensitivity threshold were observed in animals treated with EVs from either naïve MSC (MSCEvwt) or stimulated MSC (MSCEv+), with a statistically signifcant increase in threshold for MSCEv+-treated animals when compared to those that received MSCEvwt. In conclusion, these data show that treatment of acute SCI with extracellular vesicles derived from human MSCs attenuates neuroinfammation and improves functional recovery

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B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS
O'Donovan KJ et al.
JEM; May 2014

Activation of intrinsic growth programs that promote developmental axon growth may also facilitate axon regeneration in injured adult neurons. Here, we demonstrate that conditional activation of B-RAF kinase alone in mouse embryonic neurons is sufficient to drive the growth of long-range peripheral sensory axon projections in vivo in the absence of upstream neurotrophin signaling. We further show that activated B-RAF signaling enables robust regenerative growth of sensory axons into the spinal cord after a dorsal root crush as well as substantial axon regrowth in the crush-lesioned optic nerve. Finally, the combination of B-RAF gain-of-function and PTEN loss-of-function promotes optic nerve axon extension beyond what would be predicted for a simple additive effect. We conclude that cell-intrinsic RAF signaling is a crucial pathway promoting developmental and regenerative axon growth in the peripheral and central nervous systems.

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Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury
Lang BT et al.
Nature; February 2015

Contusive spinal cord injury leads to a variety of disabilities owing to limited neuronal regeneration and functional plasticity. It is well established that an upregulation of glial-derived chondroitin sulphate proteoglycans (CSPGs) within the glial scar and perineuronal net creates a barrier to axonal regrowth and sprouting. Protein tyrosine phosphatase σ (PTPσ), along with its sister phosphatase leukocyte common antigen-related (LAR) and the nogo receptors 1 and 3 (NgR), have recently been identified as receptors for the inhibitory glycosylated side chains of CSPGs. Here we find in rats that PTPσ has a critical role in converting growth cones into a dystrophic state by tightly stabilizing them within CSPG-rich substrates. We generated a membrane-permeable peptide mimetic of the PTPσ wedge domain that binds to PTPσ and relieves CSPG-mediated inhibition. Systemic delivery of this peptide over weeks restored substantial serotonergic innervation to the spinal cord below the level of injury and facilitated functional recovery of both locomotor and urinary systems. Our results add a new layer of understanding to the critical role of PTPσ in mediating the growth-inhibited state of neurons due to CSPGs within the injured adult spinal cord.

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Systemic administration of an antagonist of the ATP-sensitive receptor P2X7 improves recovery after spinal cord injury
from www.pnas.org onJuly 28, 2009

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Identification of Two Distinct Macrophage Subsets with Divergent Effects Causing either Neurotoxicity or Regeneration in the Injured Mouse Spinal Cord
from The Journal of Neuroscience, October 28, 2009

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In Vivo Magnetic Resonance Imaging of Spinal Cord Injury in the Mouse
from Journal of Neurotrauma 26:753–762 (May 2009)

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A Cluster of Cholinergic Premotor Interneurons Modulates Mouse Locomotor Activity
from Neuron 64, 645–662, December 10, 2009

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Combined Intrinsic and Extrinsic Neuronal Mechanisms Facilitate Bridging Axonal Regeneration One Year after Spinal Cord Injury
from doi: 10.1016/j.neuron.2009.09.016

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Rewiring of hindlimb corticospinal neurons after spinal cord injury
from Nature Neuroscience Volume 13 | Number 1 | January 2010

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Two Faces of Chondroitin Sulfate Proteoglycan in Spinal Cord Repair: A Role in Microglia/Macrophage Activation
from www.plosmedicine.org on August 2008

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Autologous mucosal transplant in chronic spinal cord injury: an Indian Pilot Study
from www.nature.com on June 2009

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