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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    012—Spinal Cord Injury: Mechanisms and Therapies

    Saturday, November 09, 2013, 1:00 pm - 4:30 pm

    12.03: Chondroitin sulfate proteoglycans modulate the survival and differentiation of spinal cord stem/progenitor cells

    Location: 23A

    ">S. M. DYCK, A. ALIZADEH, E. H. PROULX, *S. KARIMI-ABDOLREZAEE;
    Physiol., Univ. of Manitoba, Winnipeg, MB, Canada

    Abstract Body: Multipotent neural stem/progenitor cells (NPCs) residing in the spinal cord contain the intrinsic potential to replenish damaged oligodendrocytes after a spinal cord injury (SCI). Despite this capacity, proliferation and oligodendrocyte differentiation of NPCs is severely limited in the microenvironment of SCI. Following injury, spinal NPCs mainly differentiate into astrocytes and partly contribute to astrogliosis. This evidence emphasizes a key role for the post-SCI niche in modulating the regenerative response of spinal NPCs. We recently reported that injury-induced upregulation of chondroitin sulfate proteoglycans (CSPGs) potently restrict the survival, integration and differentiation of transplanted and endogenous NPCs in SCI. In vivo administration of chondroitinase (ChABC) promoted the long-term integration of transplanted NPCs and enhanced the activation and oligodendrocyte differentiation of resident NPCs after subacute and chronic SCI. Our new evidence shows that spinal NPCs may be directly modulated by CSPGs as they express CSPG receptors, protein tyrosine phosphate receptor sigma (PTPσ) and leukocyte common antigen-related phosphatase (LAR) both in vitro and in vivo. Given the long-lasting upregulation of CSPGs in NPCs niche after SCI, it is important to unravel the potential mechanisms by which CSPGs could influence the cell dynamics of NPCs. In primary cultures of adult spinal cord NPCs, using cell viability, western blotting, and immunocytochemistry assays, we show that CSPG substrate significantly decrease NPC attachment and survival. Moreover, exposure of spinal NPCs to CSPGs drove their fate towards an astrocytic lineage and reduced their oligodendorcyte differentiation. The effects of CSPGs on spinal cord NPCs were specific and reversed by degradation of CSPGs with ChABC treatment prior to NPCs plating. Interestingly, genetic down-regulation of PTP-σ and LAR receptors in spinal NPCs using dicer-substrate RNA (DsiRNA) technology was sufficient to attenuate the inhibitory effects of CSPGs on NPC survival and differentiation. Our data suggest the impact of CSPGs and its signaling receptors in governing the response of NPCs in their post-SCI niche, and identify new therapeutic targets for enhancing NPC-based therapies following SCI. Supported by grants from NSERC, MHRC, MMSF and HSCF.

    Lay Language Summary: Our research team endeavors to develop therapies that will provide improvement in the quality of life in patients with spinal cord injury. Spinal cord injury is one of the most devastating neurological conditions known in humans affecting over 2.5 million individuals world-wide, with approximately 130,000 new patients each ear. Spinal cord injury results in permanent disability in its victim below their level of injury. Most spinal cord injury victims are young and productive members of the community under age 30 who will require a life time of medical attention and home care. Any treatment option that provides even some improvement in function for patients may improve their quality of life significantly. As a result, there is currently a substantial incentive to develop safe and effective therapies for spinal cord injury. Extensive preclinical studies by our group and others have shown the potential of transplanting neural stem cell as a therapeutic option for treatment of the injured and diseased spinal cord. Despite the promise of neural stem cells in repairing the injured spinal cord, considerable uncertainty has remained regarding the efficacy of this strategy in promoting a meaningful neurological recovery. There are currently several challenges and gaps in the application of neural stem cells in experimental models of spinal cord injury that has prevented its translation into clinical testing. The majority of neural stem cell-based therapies have shown the inability of these cells to survive long enough after transplantation into the injured area of the spinal cord to result in any improvement. This failure is mainly attributed to the unfavorable environment that is present in the injured spinal cord tissue. We currently lack understanding of how these neural stem cells react to their host environment. To develop more appropriate stem cell therapies, we must first identify the inhibitory factors that cause the injured tissue to become a hostile environment for these stem cells. Our research has shown that a protein which is highly expressed in the matrix tissue following a spinal cord injury, namely chondroitin sulfate proteoglycan, limits the neural stem cell survival and integration. Inhibiting this protein with a treatment called chondroitinase is able to remove the chondroitin sulfate proteoglycan effect and allow neural stem cells to survive, replenish damaged neural cells and integrate in the host tissue. Furthermore, use of gene therapies to block the negative effects of chondroitin sulfate proteoglycans on neural stem cells has shown some promise in improving their functions. This provides a very promising therapeutic option for spinal cord injury victims; however, this requires further investigation to determine the functional benefits of such treatments. In summary, this research allows for a better understanding of the injured spinal cord environment. Using this gained knowledge we can develop more effective stem cell therapies for spinal cord injury in a hope that this will aid in recovery of function and quality of life in spinal cord injury patients. Moreover, knowledge gained from our research can be applied to other neurological conditions including brain injury, stroke, cerebral palsy and multiple sclerosis with similar pathological outcomes. Stem cell therapy is an exciting field that has revolutionized regenerative medicine; however, much work still needs to be done before any stem cell therapies can be translated into clinical practice.

    Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    012—Spinal Cord Injury: Mechanisms and Therapies

    Saturday, November 09, 2013, 1:00 pm - 4:30 pm

    12.03: Chondroitin sulfate proteoglycans modulate the survival and differentiation of spinal cord stem/progenitor cells

    Location: 23A

    ">S. M. DYCK, A. ALIZADEH, E. H. PROULX, *S. KARIMI-ABDOLREZAEE;
    Physiol., Univ. of Manitoba, Winnipeg, MB, Canada

    Abstract Body: Multipotent neural stem/progenitor cells (NPCs) residing in the spinal cord contain the intrinsic potential to replenish damaged oligodendrocytes after a spinal cord injury (SCI). Despite this capacity, proliferation and oligodendrocyte differentiation of NPCs is severely limited in the microenvironment of SCI. Following injury, spinal NPCs mainly differentiate into astrocytes and partly contribute to astrogliosis. This evidence emphasizes a key role for the post-SCI niche in modulating the regenerative response of spinal NPCs. We recently reported that injury-induced upregulation of chondroitin sulfate proteoglycans (CSPGs) potently restrict the survival, integration and differentiation of transplanted and endogenous NPCs in SCI. In vivo administration of chondroitinase (ChABC) promoted the long-term integration of transplanted NPCs and enhanced the activation and oligodendrocyte differentiation of resident NPCs after subacute and chronic SCI. Our new evidence shows that spinal NPCs may be directly modulated by CSPGs as they express CSPG receptors, protein tyrosine phosphate receptor sigma (PTPσ) and leukocyte common antigen-related phosphatase (LAR) both in vitro and in vivo. Given the long-lasting upregulation of CSPGs in NPCs niche after SCI, it is important to unravel the potential mechanisms by which CSPGs could influence the cell dynamics of NPCs. In primary cultures of adult spinal cord NPCs, using cell viability, western blotting, and immunocytochemistry assays, we show that CSPG substrate significantly decrease NPC attachment and survival. Moreover, exposure of spinal NPCs to CSPGs drove their fate towards an astrocytic lineage and reduced their oligodendorcyte differentiation. The effects of CSPGs on spinal cord NPCs were specific and reversed by degradation of CSPGs with ChABC treatment prior to NPCs plating. Interestingly, genetic down-regulation of PTP-σ and LAR receptors in spinal NPCs using dicer-substrate RNA (DsiRNA) technology was sufficient to attenuate the inhibitory effects of CSPGs on NPC survival and differentiation. Our data suggest the impact of CSPGs and its signaling receptors in governing the response of NPCs in their post-SCI niche, and identify new therapeutic targets for enhancing NPC-based therapies following SCI. Supported by grants from NSERC, MHRC, MMSF and HSCF.

    Lay Language Summary: Our research team endeavors to develop therapies that will provide improvement in the quality of life in patients with spinal cord injury. Spinal cord injury is one of the most devastating neurological conditions known in humans affecting over 2.5 million individuals world-wide, with approximately 130,000 new patients each ear. Spinal cord injury results in permanent disability in its victim below their level of injury. Most spinal cord injury victims are young and productive members of the community under age 30 who will require a life time of medical attention and home care. Any treatment option that provides even some improvement in function for patients may improve their quality of life significantly. As a result, there is currently a substantial incentive to develop safe and effective therapies for spinal cord injury. Extensive preclinical studies by our group and others have shown the potential of transplanting neural stem cell as a therapeutic option for treatment of the injured and diseased spinal cord. Despite the promise of neural stem cells in repairing the injured spinal cord, considerable uncertainty has remained regarding the efficacy of this strategy in promoting a meaningful neurological recovery. There are currently several challenges and gaps in the application of neural stem cells in experimental models of spinal cord injury that has prevented its translation into clinical testing. The majority of neural stem cell-based therapies have shown the inability of these cells to survive long enough after transplantation into the injured area of the spinal cord to result in any improvement. This failure is mainly attributed to the unfavorable environment that is present in the injured spinal cord tissue. We currently lack understanding of how these neural stem cells react to their host environment. To develop more appropriate stem cell therapies, we must first identify the inhibitory factors that cause the injured tissue to become a hostile environment for these stem cells. Our research has shown that a protein which is highly expressed in the matrix tissue following a spinal cord injury, namely chondroitin sulfate proteoglycan, limits the neural stem cell survival and integration. Inhibiting this protein with a treatment called chondroitinase is able to remove the chondroitin sulfate proteoglycan effect and allow neural stem cells to survive, replenish damaged neural cells and integrate in the host tissue. Furthermore, use of gene therapies to block the negative effects of chondroitin sulfate proteoglycans on neural stem cells has shown some promise in improving their functions. This provides a very promising therapeutic option for spinal cord injury victims; however, this requires further investigation to determine the functional benefits of such treatments. In summary, this research allows for a better understanding of the injured spinal cord environment. Using this gained knowledge we can develop more effective stem cell therapies for spinal cord injury in a hope that this will aid in recovery of function and quality of life in spinal cord injury patients. Moreover, knowledge gained from our research can be applied to other neurological conditions including brain injury, stroke, cerebral palsy and multiple sclerosis with similar pathological outcomes. Stem cell therapy is an exciting field that has revolutionized regenerative medicine; however, much work still needs to be done before any stem cell therapies can be translated into clinical practice.