Elucidating the role and mechanisms of CSPGs in modulating endogenous repair processes in spinal cord injury
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Date
2015-07, 2015-07, 2017-05, 2018
Authors
Dyck, Scott
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier
Frontiers
John Wiley and Sons
BioMed Central
John Wiley and Sons
Frontiers
John Wiley and Sons
BioMed Central
John Wiley and Sons
Abstract
Populations of oligodendrocytes are susceptible to cell death following spinal cord injury (SCI), which results in axon demyelination. Multipotent resident neural precursor cells (NPCs) and oligodendrocyte precursor cells (OPCs) have the innate potential to replace lost oligodendrocytes, however, their regenerative capabilities are limited within the milieu of SCI. Thus, development of therapies which promote endogenous oligodendrocyte replacement is a critical therapeutic target for SCI repair. Studies by our group have shown that upregulation of chondroitin sulfate proteoglycans (CSPGs) in the extracellular matrix appears to limit oligodendrocytes replacement after SCI. Importantly, it is known that targeting CSPGs can improve functional recovery after SCI. However, the cellular and molecular mechanisms underlying the inhibitory effects of CSPGs remain largely undefined. The discovery of CSPGs specific signaling receptors, leukocyte common antigen-related (LAR) and protein tyrosine phosphatase-sigma (PTPσ), allows us to uncover CSPGs direct mechanisms.
Using in vitro models recapitulating the extracellular matrix of SCI, we first identify that CSPGs directly impede the ability of NPCs for proliferation and oligodendrocyte differentiation by signaling through LAR and PTPσ receptors and activation of the Rho/ROCK pathway. Pharmacological inhibition of LAR with Intracellular LAR peptide (ILP) and PTPσ with Intracellular Sigma peptide (ISP) is efficient to block nearly all CSPGs effect on NPCs in vitro. Similarly, the presence of CSPGs inhibits OPCs growth, maturation and myelination in vitro, which can be overcome by inhibition of LAR and PTPσ receptors.
Capitalizing on these in vitro observation, we hypothesized that pharmacological blockage of LAR and PTPσ will promote endogenous oligodendrogenesis following SCI. Using a clinically relevant model of compressive/contusive SCI in the rat, we demonstrate that ILP and ISP play critical roles in regulating the endogenous cell response to injury. Perturbing LAR and PTPσ signaling attenuates oligodendrocyte apoptosis and myelin damage, while promoting oligodendrogenesis. We unraveled that LAR and PTPσ control oligodendrocyte differentiation partly by modulating microglia response and RhoA activity. In SCI, CSPGs contribute to the pro-inflammatory immune response by signaling through LAR and PTPσ, and that their inhibition forges a pro-regenerative inflammatory landscape characterized by interleukin-10 mediated mechanisms that fosters oligodendrocyte replacement and integrity.
Thus, our findings uncover new roles for CSPGs in regulating secondary injury mechanisms in SCI. We have identified LAR and PTPσ as novel viable targets for modulating immune response and endogenous cell replacement following SCI.
Description
Keywords
Spinal cord injury, Glial scar, Astrogliosis, CSPGs, Chondroitin sulfate proteoglycans, Cell replacement, Oligodendrocyte replacement, Oligodendrogenesis, Neuroinflammation
Citation
Scott Dyck and Soheila Karimi-Abdolrezaee. Role of Chondroitin Sulfate Proteoglycans in Development and Pathology of the Central Nervous System. Experimental Neurology. 2015 Jul;269:169-187. doi: 10.1016/j.expneurol.2015.04.006
Arsalan Alizadeh, Scott Dyck, Soheila Karimi-Abdolrezaee. Myelin Damage and repair in pathological CNS: challenge and prospects. Frontiers of Molecular Neuroscience. 2015 July 27;8:35. doi: 10.3389/fnmol.2015.00035
Scott Dyck, Arsalan Alizadeh, Santosh Thomas Kallivalappil, Chia-Lun Wu, Evan Proulx and Soheila Karimi-Abdolrezaee. Chondroitin Sulfate Proteoglycans Negatively Modulate the Properties of Adult Spinal Cord Neural Precursor Cells by Signaling through LAR and PTPσ Receptors and Activation of the Rho/ROCK Pathway. Stem Cells. 2015 Aug; 33(8): 2550-2563. doi: 10.1002/stem.1979
Scott Dyck, Hardeep Kataria†, Arsalan Alizadeh†, Kallivalappil T. Santhosh, Bradley Lang, Jerry Silver, Soheila Karimi-Abdolrezaee. Perturbing Chondroitin Sulfate Proteoglycans Signaling through LAR and PTPσ Receptors Promotes a Pro-Regenerative Inflammatory Response following Spinal Cord Injury. Journal of Neuroinflammation. Accepted March 2018
Scott Dyck, Hardeep Kataria, Bradley Lang, Jerry Silver, and Soheila Karimi-Abdolrezaee. Pharmacological Inhibition of LAR and PTPσ Signaling Promotes Oligodendrocyte Preservation and Replacement following Spinal Cord Injury. Manuscript will be submitted to GLIA in March 2018
Arsalan Alizadeh, Scott Dyck, Soheila Karimi-Abdolrezaee. Myelin Damage and repair in pathological CNS: challenge and prospects. Frontiers of Molecular Neuroscience. 2015 July 27;8:35. doi: 10.3389/fnmol.2015.00035
Scott Dyck, Arsalan Alizadeh, Santosh Thomas Kallivalappil, Chia-Lun Wu, Evan Proulx and Soheila Karimi-Abdolrezaee. Chondroitin Sulfate Proteoglycans Negatively Modulate the Properties of Adult Spinal Cord Neural Precursor Cells by Signaling through LAR and PTPσ Receptors and Activation of the Rho/ROCK Pathway. Stem Cells. 2015 Aug; 33(8): 2550-2563. doi: 10.1002/stem.1979
Scott Dyck, Hardeep Kataria†, Arsalan Alizadeh†, Kallivalappil T. Santhosh, Bradley Lang, Jerry Silver, Soheila Karimi-Abdolrezaee. Perturbing Chondroitin Sulfate Proteoglycans Signaling through LAR and PTPσ Receptors Promotes a Pro-Regenerative Inflammatory Response following Spinal Cord Injury. Journal of Neuroinflammation. Accepted March 2018
Scott Dyck, Hardeep Kataria, Bradley Lang, Jerry Silver, and Soheila Karimi-Abdolrezaee. Pharmacological Inhibition of LAR and PTPσ Signaling Promotes Oligodendrocyte Preservation and Replacement following Spinal Cord Injury. Manuscript will be submitted to GLIA in March 2018