Axonal elongation into peripheral nervous system bridges after CNS injury in adult rats

McGill University, Montréal, Quebec, Canada
Science (Impact Factor: 31.48). 11/1981; 214(4523):931-3. DOI: 10.1126/science.6171034
Source: PubMed

ABSTRACT The origin, termination, and length of axonal growth after focal central nervous system injury was examined in adult rats by means of a new experimental model. When peripheral nerve segments were used as "bridges" between the medulla and spinal cord, axons from neurons at both these levels grew approximately 30 millimeters. The regenerative potential of these central neurons seems to be expressed when the central nervous system glial environment is changed to that of the peripheral nervous system.

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Available from: Albert J. Aguayo, Aug 28, 2015
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    • "Compared to the peripheral nervous system, the failure of the adult CNS to regenerate is largely attributed to two basic aspects: inhibitory environmental influences and decreased growth capabilities of adult CNS neurons. Since early demonstration of successful growth of injured CNS axons into grafted peripheral nerve (David and Aguayo, 1981), multiple CNS axonal growth inhibitory factors have been identified and are mainly associated with degenerating CNS myelin (such as Nogo, MAG, OMgp) and with glial scar (such as chondroitin sulfate proteoglycans, CSPGs) (Yiu and He, 2006). However, blockade of these extracellular inhibitory signals alone is often insufficient for the majority of injured axons to achieve long-distance regeneration, as intrinsic regenerative capacity of mature CNS neurons is also a critical determinant for axon re-growth(Sun et al., 2011). "
    Neural Regeneration Research 10/2014; 9(19):1703-1705. DOI:10.4103/1673-5374.143412 · 0.23 Impact Factor
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    • "The limited ability of the human central nervous system (CNS) to repair itself following injuries has been known since the days of Ancient Egypt (3,000–2,5000 BCE), as documented in the Edwin Smith papyrus [1]. It had long been thought that neurons in the CNS were incapable of mounting a regenerative response, until the studies of Aguayo and colleagues in the early 1980's [2] [3] which demonstrated that certain classes of neurons within the CNS, particularly those neurons which sustained an axonal injury in close proximity to their cell body, were able to regenerate their axons within a permissive environment, such as a peripheral nerve graft. Aguayo's work and more recent studies [4] [5] [6] have all demonstrated that supraspinal neurons (neurons arising in the cerebral cortex or brainstem and which project their axons caudally into the spinal cord) are actually capable of mounting a regenerative, albeit brief, and response following injury, when provided with the proper environment. "
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    ABSTRACT: Chondroitin sulfate proteoglycans (CSPGs) are widely expressed in the normal central nervous system, serving as guidance cues during development and modulating synaptic connections in the adult. With injury or disease, an increase in CSPG expression is commonly observed close to lesioned areas. However, these CSPG deposits form a substantial barrier to regeneration and are largely responsible for the inability to repair damage in the brain and spinal cord. This review discusses the role of CSPGs as inhibitors, the role of inflammation in stimulating CSPG expression near site of injury, and therapeutic strategies for overcoming the inhibitory effects of CSPGs and creating an environment conducive to nerve regeneration.
    BioMed Research International 09/2014; 2014:845323. DOI:10.1155/2014/845323 · 2.71 Impact Factor
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    • "produced is essential since it impedes repair and exacerbates disease by arresting the regeneration of severed adult axons (David and Aguayo, 1981), preventing remyelination (Kotter et al., 2006) and advancing the production of membrane attack complexes that damage nearby intact tissue (Mead et al., 2002). Thus, understanding how SIRPα inhibits the phagocytosis of degenerated myelin is of utmost importance. "
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    ABSTRACT: The innate-immune function of phagocytosis of apoptotic cells, tissue-debris, pathogens and cancer cells is essential for homeostasis, tissue repair, fighting infection and combating malignancy. Phagocytosis is carried out in the CNS by resident microglia and in both CNS and PNS by recruited macrophages. While phagocytosis proceeds, bystander healthy cells protect themselves by sending a “do not eat me” message to phagocytes as CD47 on their surface ligates immune inhibitory receptor SIRPα on the surface of phagocytes and SIRPα then produces the signaling which inhibits phagocytosis. This helpful mechanism becomes harmful when tissue-debris and unhealthy cells inhibit their own phagocytosis by employing the same mechanism. However, the inhibitory signaling that SIRPα produces has not been fully revealed. We focus here on how SIRPα inhibits the phagocytosis of the tissue-debris “degenerated-myelin” which hinders repair in axonal injury and neurodegenerative diseases. We tested whether SIRPα inhibits phagocytosis by regulating cytoskeleton function through paxillin and cofilin since (a) the cytoskeleton generates the mechanical forces that drive phagocytosis and (b) both paxillin and cofilin control cytoskeleton function. Paxillin and cofilin were transiently activated in microglia as phagocytosis was activated. In contrast, paxillin and cofilin were continuously activated and phagocytosis augmented in microglia in which SIRPα expression was knocked-down by SIRPα-shRNA. Further, levels of phagocytosis, paxillin activation and cofilin activation positively correlated with one another. Taken together, these observations suggest a novel mechanism whereby paxillin and cofilin are targeted to control phagocytosis by both the activating signaling that phagocytic receptors produce by promoting the activation of paxillin and cofilin and the inhibiting signaling that immune inhibitory SIRPα produces by promoting the inactivation of paxillin and cofilin.
    Frontiers in Cellular Neuroscience 04/2014; 8:104. DOI:10.3389/fncel.2014.00104 · 4.18 Impact Factor
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