Optic axons regenerate into sciatic nerve isografts only in the presence of Schwann cells

Berry, Martin; Rees, L.; Hall, Susan; Yiu, Pakman; Sievers, Jobst

doi:10.1016/0361-9230(88)90182-7

Cited by 125 publications

(48 citation statements)

References 47 publications

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“…Furthermore, the elimination of viable Schwann cells from peripheral nerve grafts abolishes the promotion of CNS regeneration [39][40][41]. Transplantation of Schwann cells into sites of CNS injury, including the lesioned spinal cord, mimics the effects of peripheral nerve grafts and supports axonal regeneration [42,43].…”

Section: Provision Of Growth-promoting Substrates To Sites Of Injurymentioning

confidence: 99%

Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

Hollis

Tuszynski

2011

Neurotherapeutics

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Spinal cord injury permanently disrupts neuroanatomical circuitry and can result in severe functional deficits. These functional deficits, however, are not immutable and spontaneous recovery occurs in some patients. It is highly likely that this recovery is dependent upon spared tissue and the endogenous plasticity of the central nervous system. Neurotrophic factors are mediators of neuronal plasticity throughout development and into adulthood, affecting proliferation of neuronal precursors, neuronal survival, axonal growth, dendritic arborization and synapse formation. Neurotrophic factors are therefore excellent candidates for enhancing axonal plasticity and regeneration after spinal cord injury. Understanding growth factor effects on axonal growth and utilizing them to alter the intrinsic limitations on regenerative growth will provide potent tools for the development of translational therapeutic interventions for spinal cord injury.Keywords Neurotrophin . spinal cord injury . regeneration . axon plasticity . functional recovery Human Spinal Cord InjuryTraumatic injury of the spinal cord can produce a range of debilitating effects and permanently alter the capabilities and quality of life of its surviving victims. Damage to the central nervous system (CNS) in general results in destruction of neuronal circuitry. Contusion, compression, and penetration injuries of the spinal cord can interrupt the flow of sensory and motor information between the brain and periphery [1]. Depending on the location and severity of the injury, deficits can range from weakness of limb movement to total paralysis and ventilator-assisted respiration. Spontaneous functional recovery is limited, but can and often does occur in patients with initial sparing of sensorimotor function [2]. This recovery, which plateaus between 12 to 18 months, is very likely due to sparing and sprouting of axons within the zone of partial preservation, an area where some motor function remains intact, immediately adjacent to the lesion site [2].Approximately 40% of humans that sustain spinal cord injury (SCI) exhibit improvement from their early postinjury baseline, and this spontaneous recovery can range from modest to extensive [2]. Spontaneous recovery primarily appears to depend on the extent of tissue sparing at the injury site, allowing compensatory axonal sprouting and systems reorganization at levels ranging from the spinal cord to the cerebral cortex [3][4][5][6][7][8][9][10]. However, in cases of more severe injuries, means of enhancing endogenous levels of axonal sprouting and inducing true axonal regeneration are required to enhance functional outcomes.Electronic supplementary material The online version of this article

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Section: Provision Of Growth-promoting Substrates To Sites Of Injurymentioning

confidence: 99%

Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

Hollis

Tuszynski

2011

Neurotherapeutics

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“…A peripheral nerve segment grafted to the optic nerve promotes partial survival and regeneration of rat retinal ganglion cells (RGCs) (4). This effect is supposed to be due to nonneuronal cells, presumably SCs, present in the graft (4,5). The positive effect of SCs on regeneration and survival of injured neurons is believed to be due to the production of supportive or neuronotrophic molecules, or both.…”

mentioning

confidence: 99%

Schwann cells promote the survival of rat retinal ganglion cells after optic nerve section.

Maffei

Carmignoto

Perry

et al. 1990

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

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Schwann cells (SCs) are known to play an important role for the regeneration of mammalian peripheral nerves. Their effect is likely due to the production of neuronotrophic and/or supportive factors. Here we study the effect of intraocular transplant of SCs on the survival of rat retinal ganglion cells (RGCs) after the intracranial section of the optic nerve. SCs were injected intraocularly in adult hooded rats. Surviving RGCs were retrogradely labeled with horseradish peroxidase applied to the proximal stump of the optic nerve. Results show that intraocular transplants of SCs promote the survival of a large number ofRGCs for periods as long as 9 and 14 weeks after optic nerve section. In experimental retinae, surviving RGCs were 2-to 8-fold more numerous than in controls. This finding suggests that SCs are the source of factors that promote the survival ofRGCs. Nerve growth factor is produced by SCs, and the intraocular injection of nerve growth factor has been previously shown to promote RGC survival. The rescuing effect of SCs on RGCs is greater than that obtained by intraocular injection of nerve growth factor. This greater effect may be due to the action of other neurotrophic factors produced by SCs or by transplanted SCs producing NGF in a sustained fashion.The limited capacity of central nervous system (CNS) neurons to regenerate is thought to be due in part to the presence of nonpermissive factors such as myelin-producing oligodendrocytes (1) or to the absence of neurotrophic factors, or to both (2). In the peripheral nervous system, where regeneration takes place, Schwann cells (SCs) play an important role in promoting regeneration (3). To some extent they also can promote regeneration of CNS neurons. A peripheral nerve segment grafted to the optic nerve promotes partial survival and regeneration of rat retinal ganglion cells (RGCs) (4). This effect is supposed to be due to nonneuronal cells, presumably SCs, present in the graft (4, 5). The positive effect of SCs on regeneration and survival of injured neurons is believed to be due to the production of supportive or neuronotrophic molecules, or both. For instance, there is evidence indicating that SCs produce nerve growth factor (NGF) or a NGF-like protein in vitro (6) and after peripheral nerve injury in vivo (7,8). Recently, it has been shown that repetitive intraocular injections of NGF enhance the survival of axotomized rat RGCs (9). In the present study we test the hypothesis that intraocular transplant of SCs promotes the survival of rat RGCs after axotomy.Our results show that SCs are dramatically effective in rescuing RGCs from degeneration. Whereas in control retinae only 5% of the total population of RGCs survive 9 weeks after optic nerve section, in experimental retinae survival of RGCs was enhanced 2-to 8-fold. In experimental retinae RGCs also display a normal soma size. Hamilton syringe. The tip of the needle was inserted under microscopic guidance through the dorsal limbus of the eye. The injection was performed several days before...

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“…Although ECM from nerve or muscle appears to support peripheral nerve regeneration (1,35), there is some controversy regarding the relative efficacy of cell-cell and cellmatrix interactions in vivo (36)(37)(38). In our studies, coating nerve tubes with laminin significantly enhanced regeneration ( Fig.…”

Section: Resultsmentioning

confidence: 56%

“…Sci. USA 87 (1990) reason for this partial inhibition in vivo is unclear (20 (17,39) and possibly in vivo (36)(37)(38).…”

Section: Resultsmentioning

confidence: 99%

A dual laminin/collagen receptor acts in peripheral nerve regeneration.

Toyota

Carbonetto

David

1990

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

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A regeneration chamber was created in vivo by suturing a synthetic tube sealed at its distal end onto the proximal stump of a severed rat sciatic nerve. Nerves regenerated into tubes coated with laminin at a rate of 0.33 mm/day after a lag of about 2 days. At 25 days, regenerating nerves had extended 23% farther into laminin-coated tubes as compared with uncoated ones. Monoclonal antibody 3A3, which functionally interferes with a dual lanminin/collagen receptor, inhibited nerve regeneration into laminin-coated tubes by 32%. In contrast, monoclonal antibody JG22, which inhibits chicken matrix receptors, had no significant effect on regeneration. Immunohistochemical studies of teased adult rat sciatic nerves indicate that 3A3 bound to Schwann cells and possibly to axons. In other studies, the heterodimeric, laminin/collagen receptor recognized by 3A3 has been shown to be a member of the integrin superfamily of adhesive receptors. These data provide evidence that an integrin receptor functions in nerve regeneration in vivo.In adult mammals, damaged axons can regenerate for many centimeters within the peripheral nervous system. These regenerating axons are typically found within conduits of basement membranes, often in contact with Schwann cells (1, 2). Like many other basement membranes, those in the peripheral nervous system are comprised of laminin, collagen, fibronectin, and other extracellular matrix (ECM) components (3-7). In culture, purified fibronectin, collagen, and especially laminin stimulate outgrowth as well as guide nerve processes (8)(9)(10)(11)(12). This growth requires binding of cell-surface receptors to ECM adhesive proteins. Several ECM receptors and binding proteins have been identified, most notably a superfamily of heterodimeric proteins called integrins. Integrins are found in a wide variety of cell types where they mediate both cell-cell and cell-matrix adhesion (13-15). Of particular note are observations that integrins mediate neurite outgrowth in culture (16)(17)(18)(19).Prompted by recent studies implicating laminin in nerve regeneration in vivo (20, 21), we have sought to identify ECM receptors responsible for matrix-mediated nerve regeneration. To accomplish this, we have employed a method for isolating in vivo regenerating peripheral nerves within synthetic tubes (21-24). Peripheral nerves are severed, and their proximal stumps are capped with a tube sealed at its distal end (24) to form a chamber. The tubes are then filled with a solution containing monoclonal antibody (mAb) 3A3 (IgGl), which inhibits neurite outgrowth by PC12 cells (a rat pheochromocytoma cell line) on laminin and collagen culture substrata (25). It has been shown elsewhere (25) that mAb 3A3 binds to a heterodimeric receptor complex (185 kDa, 125 kDa) of the integrin superfamily. mAb 3A3 appears to recognize the a subunit of this laminin/collagen receptor, which can be immunoprecipitated from detergent extracts not only of PC12 cells but also of embryonic rat neural tissues (26). We show here that (i) lamin...

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Optic axons regenerate into sciatic nerve isografts only in the presence of Schwann cells

Cited by 125 publications

References 47 publications

Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

Schwann cells promote the survival of rat retinal ganglion cells after optic nerve section.

A dual laminin/collagen receptor acts in peripheral nerve regeneration.

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