Abstract
BackgroundChondroitin sulfate proteoglycan (CSPG) is a major component of the glial scar. It is considered to be a major obstacle for central nervous system (CNS) recovery after injury, especially in light of its well-known activity in limiting axonal growth. Therefore, its degradation has become a key therapeutic goal in the field of CNS regeneration. Yet, the abundant de novo synthesis of CSPG in response to CNS injury is puzzling. This apparent dichotomy led us to hypothesize that CSPG plays a beneficial role in the repair process, which might have been previously overlooked because of nonoptimal regulation of its levels. This hypothesis is tested in the present study.Methods and FindingsWe inflicted spinal cord injury in adult mice and examined the effects of CSPG on the recovery process. We used xyloside to inhibit CSPG formation at different time points after the injury and analyzed the phenotype acquired by the microglia/macrophages in the lesion site. To distinguish between the resident microglia and infiltrating monocytes, we used chimeric mice whose bone marrow-derived myeloid cells expressed GFP. We found that CSPG plays a key role during the acute recovery stage after spinal cord injury in mice. Inhibition of CSPG synthesis immediately after injury impaired functional motor recovery and increased tissue loss. Using the chimeric mice we found that the immediate inhibition of CSPG production caused a dramatic effect on the spatial organization of the infiltrating myeloid cells around the lesion site, decreased insulin-like growth factor 1 (IGF-1) production by microglia/macrophages, and increased tumor necrosis factor alpha (TNF-α) levels. In contrast, delayed inhibition, allowing CSPG synthesis during the first 2 d following injury, with subsequent inhibition, improved recovery. Using in vitro studies, we showed that CSPG directly activated microglia/macrophages via the CD44 receptor and modulated neurotrophic factor secretion by these cells.ConclusionsOur results show that CSPG plays a pivotal role in the repair of injured spinal cord and in the recovery of motor function during the acute phase after the injury; CSPG spatially and temporally controls activity of infiltrating blood-borne monocytes and resident microglia. The distinction made in this study between the beneficial role of CSPG during the acute stage and its deleterious effect at later stages emphasizes the need to retain the endogenous potential of this molecule in repair by controlling its levels at different stages of post-injury repair.
Highlights
The poor recovery of the central nervous system (CNS) following an injury is generally attributed to the accumulation of compounds that mediate self-perpetuating degeneration, the presence of growth inhibitors [1,2], formation of the glial scar [3,4], and a malfunction of the immune response mediated mostly by microglia/macrophages [5,6,7,8]
Our results show that Chondroitin sulfate proteoglycan (CSPG) plays a pivotal role in the repair of injured spinal cord and in the recovery of motor function during the acute phase after the injury; CSPG spatially and temporally controls activity of infiltrating blood-borne monocytes and resident microglia
The distinction made in this study between the beneficial role of CSPG during the acute stage and its deleterious effect at later stages emphasizes the need to retain the endogenous potential of this molecule in repair by controlling its levels at different stages of post-injury repair
Summary
The poor recovery of the central nervous system (CNS) following an injury is generally attributed to the accumulation of compounds that mediate self-perpetuating degeneration, the presence of growth inhibitors [1,2], formation of the glial scar [3,4], and a malfunction of the immune response mediated mostly by microglia/macrophages [5,6,7,8]. It is apparent that the phenotype of microglia/macrophages is not uniform [15,18,19,20,21,22,23,24], and that in response to different stimuli these cells can acquire either destructive [25,26,27,28,29,30,31] or a beneficial phenotype [32,33,34] These latter observations, together with the fact that the postinjury increase in CSPG is not restricted to the CNS but is a general phenomenon associated with the healing of wounds [35], led us to postulate that the intense de novo synthesis of CSPG following injury might have a role in the repair process by regulating the local immune response, and that its overall negative reputation might reflect nonoptimal regulation of its production and/or degradation. Because damaged axons rarely regrow, most spinal cord injuries are permanent
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