Regenerating Fish Optic Nerves and a Regeneration-Like Response in Injured Optic Nerves of Adult Rabbits

Schwartz, Michal; Belkin, Michael; Harel, A.; Solomon, Arieh S.; Lavie, Vered; Hadani, Moshe; Rachailovich, I.; Stein-Izsak, C

doi:10.1126/science.3983646

Cited by 77 publications

(36 citation statements)

References 19 publications

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“…Monoclonal antibodies directed against the inhibitory molecules were shown to neutralize the growthinhibitory effect (10). In line with these observations is our finding that the high regenerative capacity of the fish optic nerve is correlated with the presence of a factor or factors cytotoxic to oligodendrocytes (12)(13)(14). This factor(s) was detected among the soluble substances derived from regenerating fish optic nerves, which were collectively termed conditioned medium (CM) and, when applied in vivo, helped to create conditions conducive to axonal growth in other species-e.g., in injured optic nerves of rabbit (15,16).…”

supporting

confidence: 76%

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Identification of an interleukin 2-like substance as a factor cytotoxic to oligodendrocytes and associated with central nervous system regeneration.

Eitan

Zisling

Cohen

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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Axons of the central nervous system in adult mammals do not regenerate spontaneously after injury, partly because of the presence of oligodendrocytes that inhibit axonal growth. This is not the case in lower vertebrates (e.g., in fish), where regeneration of the optic nerve does occur spontaneously and has been correlated with the presence of factors cytotoxic to oligodendrocytes. The present study provides evidence that the substance originating from the fish optic nerves, which is cytotoxic to oligodendrocytes, is an interleukin 2-like substance.Axons of the central nervous system (CNS) in lower vertebrates regenerate after injury (1-4). Considerable research interest has recently been focused on the oligodendrocytes. It was shown that mature oligodendrocytes create an environment that is nonpermissive for growth (9). Monoclonal antibodies directed against the inhibitory molecules were shown to neutralize the growthinhibitory effect (10). In line with these observations is our finding that the high regenerative capacity of the fish optic nerve is correlated with the presence of a factor or factors cytotoxic to oligodendrocytes (12)(13)(14). This factor(s) was detected among the soluble substances derived from regenerating fish optic nerves, which were collectively termed conditioned medium (CM) and, when applied in vivo, helped to create conditions conducive to axonal growth in other species-e.g., in injured optic nerves of rabbit (15, 16). Recent studies in our laboratory suggest that the cytotoxic factor(s) in the fish might be associated with the postinjury inflammatory reaction-i.e., with the early invasion of injured nerves by blood-derived cells (14). In the present study, the cytotoxic factor was identified as an interleukin 2 (IL-2)-like molecule. MATERIALS AND METHODSPreparation of Soluble Substances Derived from Regenerating Fish Optic Nerves. Carp (Cyprinus carpio, 800-1200 g; Tnuva, Israel) were anesthetized with 0.05% 3-aminobenzoic acid ethyl ester (Sigma), and their optic nerves were crushed with forceps (for 30 sec). Eight days later, the nerves were removed by dissection and incubated in serum-free medium for 1.5 hr (four nerve segments per 300 pLI of medium) at 250C (15). The resulting medium, defined as CM, was then collected, and its protein content was determined by the Bradford assay (17).Preparation of Medium Conditioned by Fish Lymphocytes. Fish were anesthetized with 3-aminobenzoic acid ethyl ester (Sigma). Blood was withdrawn from the venous plexus of the eye orbit and was collected (usually 30 ml from two or three fish) from the socket into a tube containing heparin sulfate (100 units/ml; BDH Chemicals). The blood was diluted with an equal volume of phosphate-buffered saline (PBS) and allowed to stand for 5 min before being layered on top of the Percoll solution [30 ml of diluted blood was carefully layered on top of the solution in a 50-ml sterilized Corex (Corning) centrifuge tube by using a small pipet]. The tubes were capped and centrifuged in swinging buckets at 800 x g ...

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supporting

confidence: 76%

“…Independently, we showed that in vitro this preparation possesses a number of activities, including cytotoxicity to mature oligodendrocytes of both fish and rat (12)(13)(14). The observed correlation between the level of the cytotoxic factor and axonal regeneration in the fish strongly suggested an association between them (14).…”

Section: Discussionmentioning

confidence: 71%

Identification of an interleukin 2-like substance as a factor cytotoxic to oligodendrocytes and associated with central nervous system regeneration.

Eitan

Zisling

Cohen

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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“…Consequently, the cell body fails to reestablish the contact with its end organ and, subsequently, degenerates as well. The posttraumatic degeneration delaying effect of the low energy laser irradiation can be potentially utilized to facilitate regeneration before irreversible degeneration and scarring sets in 21 . This beneficial effect has been exploited successfully in treatments aiming at regeneration' 4 .…”

Section: Discussionmentioning

confidence: 99%

Low Power Laser Irradiation Effect with Emphasis on Injured Neural Tissues.

Schwartz¹

1993

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“…Recent observations have offered new clues as to why the adult CNS fails to regenerate (1)(2)(3)(4)(5)(6). It appears that the environment of the injured neuron is involved in determining the ability of the neuron to regenerate after injury.…”

mentioning

confidence: 99%

“…Studies in our laboratory have demonstrated that, in the regenerating optic nerves of fish, there are alterations in the amount of several diffusible polypeptides, the most pronounced being a 28-kDa polypeptide (13), and in the ability of diffusible substances derived from regenerating nerve to trigger a regeneration-like response in a nonregenerative system (2). Regeneration-like activity was induced when diffusible substances were applied around injured optic nerves of adult rabbits, in the form of conditioned medium adsorbed to silicone tubes filled with collagen.…”

mentioning

confidence: 99%

Environmental changes induced by growth-associated triggering factors in injured optic nerve of adult rabbit.

Bawnik¹,

Harel²,

Stein-Izsak³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

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Central nervous system (CNS) neurons of mammals regenerate poorly after axonal injury. However, if an injured CNS neuron (rabbit optic nerve) is supplied with appropriate soluble substances ("growth-associated triggering factors") derived from medium conditioned by regenerating fish optic nerve or newborn rabbit optic nerve, it can express regeneration-associated characteristics. Such characteristics include a general increase in protein synthesis, changes in synthesis of specific polypeptides, and sprouting of nerve fibers in culture. The present study of rabbit optic nerves demonstrates that such active substances affect the neuronal environment (i.e., the non-neuronal cells), thereby perhaps causing a shift in the environment from an inhibitory to a regenerative supportive one. Apparently, such an environment is spontaneously achieved in injured CNS nerves of lower vertebrates (e.g., fish optic nerves), which are regenerable. Treatment of injured rabbit optic nerve with soluble factors from medium conditioned by regenerating carp optic nerve resulted in a selective increase in proliferation ([3H]thymidine incorporation) of perineural cells and the appearance of a 12-kDa polypeptide in a homogenate derived from the nerve and its associated cells. This polypeptide may be related to growth, since it comigrates in NaDodSO4/polyacrylamide gel electrophoresis with a 12-kDa polypeptide that is continuously present in a regenerative system. In addition, there were injuryinduced changes in the polypeptides of the nerve that were independent of treatment with conditioned medium and were correlated with nerve maturation. The most prominent changes of this type were in 18-kDa and 25-kDa polypeptides whose levels were reduced after injury and were found to be correlated with the nerve maturation (myelination) state.The loss of function that results from damage to the central nervous system (CNS) of mammals is due to the low regenerative potential of the mammalian CNS. Recent observations have offered new clues as to why the adult CNS fails to regenerate (1-6). It appears that the environment of the injured neuron is involved in determining the ability of the neuron to regenerate after injury. The contribution of the environment (i.e., the non-neuronal cells) to the process of regeneration is possibly in provision of diffusible substances (7, 8) and a proper extracellular matrix needed to induce and support the regenerative cascade (6, 9).Studies carried out in regenerative peripheral (sciatic nerve of rat) and central (optic nerve of fish) nerves have provided evidence that injury causes changes in the type and amount of diffusible molecules originating from non-neuronal cells surrounding the injured nerves. In the peripheral nervous system, a 37-kDa polypeptide was found to be selectively accumulated following injury to the sciatic nerve (10) and was identified recently as a form of apolipoprotein E (11, 12).Studies in our laboratory have demonstrated that, in the regenerating optic nerves of fish, there are alte...

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Regenerating Fish Optic Nerves and a Regeneration-Like Response in Injured Optic Nerves of Adult Rabbits

Cited by 77 publications

References 19 publications

Identification of an interleukin 2-like substance as a factor cytotoxic to oligodendrocytes and associated with central nervous system regeneration.

Identification of an interleukin 2-like substance as a factor cytotoxic to oligodendrocytes and associated with central nervous system regeneration.

Low Power Laser Irradiation Effect with Emphasis on Injured Neural Tissues.

Environmental changes induced by growth-associated triggering factors in injured optic nerve of adult rabbit.

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