Failed central nervous system regeneration

Immunity is required to eliminate dangerous or degenerated material and to support regeneration, but also causes significant parenchymal damage. In the eye and the brain, in which cornea and lens poorly regenerate and neurons are hardly replaceable, early transplantation experiments demonstrated remarkable tolerance to various grafts. This "immunologically privileged status" (Billingham and Boswell, 1953) may reflect evolutionary pressure to downmodulate certain actions of immune cells within particularly vulnerable tissues. As an example, tolerating certain "neurotrophic" viruses may often be a more successful strategy for survival than the elimination of all infected neurons. While several constitutive and inducible signals maintaining or re-establishing immune tolerance within the brain have been identified, it has also become evident that the resulting anti-inflammatory environment limits certain beneficial effects of neuroinflammation such as neurotrophin secretion or glutamate buffering by T-cells and the clearance of growth-inhibiting myelin or amyloid. Following spinal cord injury, the costs and benefits of neuroinflammation seem to come close because enhancing as well as suppressing innate or adaptive immunity caused amelioration and aggravation of functional regeneration in similar experiments. Evaluating such balances has also begun in (animal models of) Alzheimer's disease, central nervous system trauma, and stroke, and the appreciation of the beneficial side of neuroinflammation has caused a rethinking of the ill-defined use of immune suppressants. As dual roles for individual molecules have been recognized (Merrill and Benveniste, 1996), we are uncovering an already fine-tuned system, but the challenge remains to further support beneficial immune cascades without causing additional damage, and vice versa.     

Endogenous bioelectric fields: a putative regulator of wound repair and regeneration in the central nervous system

Studies on a variety of highly regenerative tissues, including the central nervous system(CNS) in non-mammalian vertebrates, have consistently demonstrated that tissue damage induces the formation of an ionic current at the site of injury. These injury currents generate electric fields(EF) that are 100-fold increased in intensity over that measured for uninjured tissue. In vitro and in vivo experiments have convincingly demonstrated that these electric fields(by their orientation, intensity and duration) can drive the migration, proliferation and differentiation of a host of cell types. These cellular behaviors are all necessary to facilitate regeneration as blocking these EFs at the site of injury inhibits tissue repair while enhancing their intensity promotes repair. Consequently, injury-induced currents, and the EFs they produce, represent a potent and crucial signal to drive tissue regeneration and repair. In this review, we will discuss how injury currents are generated, how cells detect these currents and what cellular responses they can induce. Additionally, we will describe the growing evidence suggesting that EFs play a key role in regulating the cellular response to injury and may be a therapeutic target for inducing regeneration in the mammalian CNS.     

Astrocytes and axon regeneration in the central nervous system

The failure of axons to regenerate in the central nervous system is mainly due to inhibition by the environment, made up of astrocytes and oligodendrocytes, which surrounds regions of damage. Both cell types are inhibitory to axon regeneration, and it seems likely that each will have to be neutralised before significant axon regeneration is achieved. Axons regenerate over the surface of astrocytes grown in normal mononlayer culture but not through three-dimensional astrocyte cultures. Astrocyte cell lines have been created, some of which resemble embryonic astrocytes and form a loose tissue with extensive extracellular space which permits axon regeneration, and others which model astrocytes in the damaged brain having little extracellular space and much extracellular matrix material. There is no correlation between the inhibitory effect on axons and the expression of cell adhesion molecules, proteases, protease inhibitors, and a variety of extracellular matrix molecules. However, extracellular matrix produced by inhibitory cell lines is inhibitory to axon regeneration, while that produced by permissive cell lines is not. This difference depends on the production of a chondroitinase-sensitive proteoglycan which can block the neurite-inducing effects of laminin so that treatment of inhibitory extracellular matrix with chondroitinase renders it more permissive to axon regeneration.     

Current concepts in central nervous system regeneration

A dictum long-held has stated that the adult mammalian brain and spinal cord are not capable of regeneration after injury. Recent discoveries have, however, challenged this dogma. In particular, a more complete understanding of developmental neurobiology has provided an insight into possible ways in which neuronal regeneration in the central nervous system may be encouraged. Knowledge of the role of neurotrophic factors has provided one set of strategies which may be useful in enhancing CNS regeneration. These factors can now even be delivered to injury sites by transplantation of genetically modified cells. Another strategy showing great promise is the discovery and isolation of neural stem cells from adult CNS tissue. It may become possible to grow such cells in the laboratory and use these to replace injured or dead neurons. The biological and cellular basis of neural injury is of special importance to neurosurgery, particularly as therapeutic options to treat a variety of CNS diseases becomes greater.     

Dental pulp stem cells and their potential roles in central nervous system regeneration and repair

Functional recovery from injuries to the brain or spinal cord represents a major clinical challenge. The transplantation of stem cells, traditionally isolated from embryonic tissue, may help to reduce damage following such events and promote regeneration and repair through both direct cell replacement and neurotrophic mechanisms. However, the therapeutic potential of using embryonic stem/progenitor cells is significantly restricted by the availability of embryonic tissues and associated ethical issues. Populations of stem cells reside within the dental pulp, representing an alternative source of cells that can be isolated with minimal invasiveness, and thus should illicit fewer moral objections, as a replacement for embryonic/fetal‐derived stem cells. Here we discuss the similarities between dental pulp stem cells (DPSCs) and the endogenous stem cells of the central nervous system (CNS) and their ability to differentiate into neuronal cell types. We also consider in vitro and in vivo studies demonstrating the ability of DPSCs to help protect against and repair neuronal damage, suggesting that dental pulp may provide a viable alternative source of stem cells for replacement therapy following CNS damage. © 2013 Wiley Periodicals, Inc.     

Autoimmunity and central nervous system regeneration in urodele amphibians

Spinal cord lesion in newt is followed by complete cell and fibre regeneration. Previous observations showed that the presence of a granuloma due to a foreign substance (talcum) in the vicinity of the cut spinal cord slows down and/or prevents regeneration. The present experiments, while confirming previous evidence, show that, in animals with a paraspinal granuloma or a subcutaneous granuloma containing an autoplastic and homoplastic spinal cord implant, immunocomplexes appear on the cut ends as has been observed by the same authors in animals in which spinal cord regeneration does not occur (Mammals). The authors discuss the results in view of their theory of the autoimmune nature of the absence of axonal regeneration.     

Growth factors for neuronal survival and process regeneration. Implications in the mammalian central nervous system

Within the past several years a number of substances have been identified in the mammalian brain that are capable of (1) preventing the death of injured neurons and (2) promoting the regeneration of severed neuronal processes. The goal of this review article is to update the clinical neurologist in this area by presenting a brief, general overview of this subject, including a glimpse at potential clinical implications. Recent advances in neuronal transplantation and molecular techniques underlying nerve growth are discussed. Possible therapeutic approaches are presented for many neurologic disorders, ranging from stroke to Alzheimer's disease to acquired immunodeficiency syndrome, based on regrowing or saving injured neurons. The clinical neurologist will become important in practical applications and research into prolonging neuronal survival and fostering axonal regeneration. Over the coming years, with further research, it is anticipated that patients will be treated with these or similar modulatory agents.     

Neurotrophic factors and corneal nerve regeneration

The cornea has unique features that make it a useful model for regenerative medicine studies. It is an avascular, transparent, densely innervated tissue and any pathological changes can be easily detected by slit lamp examination. Corneal sensitivity is provided by the ophthalmic branch of the trigeminal nerve that elicits protective reflexes such as blinking and tearing and exerts trophic support by releasing neuromediators and growth factors. Corneal nerves are easily evaluated for both function and morphology using standard instruments such as corneal esthesiometer and in vivo confocal microscope. All local and systemic conditions that are associated with damage of the trigeminal nerve cause the development of neurotrophic keratitis, a rare degenerative disease. Neurotrophic keratitis is characterized by impairment of corneal sensitivity associated with development of persistent epithelial defects that may progress to corneal ulcer, melting and perforation. Current neurotrophic keratitis treatments aim at supporting corneal healing and preventing progression of corneal damage. Novel compounds able to stimulate corneal nerve recovery are in advanced development stage. Among them, nerve growth factor eye drops showed to be safe and effective in stimulating corneal healing and improving corneal sensitivity in patients with neurotrophic keratitis. Neurotrophic keratitis represents an useful model to evaluate in clinical practice novel neuro-regenerative drugs.     

The glial scar and central nervous system repair

Damage to the central nervous system (CNS) results in a glial reaction, leading eventually to the formation of a glial scar. In this environment, axon regeneration fails, and remyelination may also be unsuccessful. The glial reaction to injury recruits microglia, oligodendrocyte precursors, meningeal cells, astrocytes and stem cells. Damaged CNS also contains oligodendrocytes and myelin debris. Most of these cell types produce molecules that have been shown to be inhibitory to axon regeneration. Oligodendrocytes produce NI250, myelin-associated glycoprotein (MAG), and tenascin-R, oligodendrocyte precursors produce NG2 DSD-1/phosphacan and versican, astrocytes produce tenascin, brevican, and neurocan, and can be stimulated to produce NG2, meningeal cells produce NG2 and other proteoglycans, and activated microglia produce free radicals, nitric oxide, and arachidonic acid derivatives. Many of these molecules must participate in rendering the damaged CNS inhibitory for axon regeneration. Demyelinated plaques in multiple sclerosis consists mostly of scar-type astrocytes and naked axons. The extent to which the astrocytosis is responsible for blocking remyelination is not established, but astrocytes inhibit the migration of both oligodendrocyte precursors and Schwann cells which must restrict their access to demyelinated axons.     

Metallothionein in the central nervous system: Roles in protection, regeneration and cognition

Metallothionein (MT) is an enigmatic protein, and its physiological role remains a matter of intense study and debate 50 years after its discovery. This is particularly true of its function in the central nervous system (CNS), where the challenge remains to link its known biochemical properties of metal binding and free radical scavenging to the intricate workings of brain. In this compilation of four reports, first delivered at the 11th International Neurotoxicology Association (INA-11) Meeting, June 2007, the authors present the work of their laboratories, each of which gives an important insight into the actions of MT in the brain. What emerges is that MT has the potential to contribute to a variety of processes, including neuroprotection, regeneration, and even cognitive functions. In this article, the properties and CNS expression of MT are briefly reviewed before Dr Hidalgo describes his pioneering work using transgenic models of MT expression to demonstrate how this protein plays a major role in the defence of the CNS against neurodegenerative disorders and other CNS injuries. His group's work leads to two further questions, what are the mechanisms at the cellular level by which MT acts, and does this protein influence higher order issues of architecture and cognition? These topics are addressed in the second and third sections of this review by Dr West, and Dr Levin and Dr Eddins, respectively. Finally, Dr Aschner examines the ability of MT to protect against a specific toxicant, methylmercury, in the CNS.     

Molecular targets to promote central nervous system regeneration

Trauma in the adult mammalian central nervous system (CNS) results in devastating clinical consequences due to the failure of injured axons to spontaneously regenerate. This regenerative failure can be attributed to both a lack of positive cues and to the presence of inhibitory cues that actively prevent regeneration. Substantial progress has been made in elucidating the molecular identity of negative cues present at the CNS injury site following injury. In the past several years, multiple myelin-associated inhibitors including Nogo, Myelin-associated glycoprotein and Oligodendrocyte-myelin glycoprotein have been characterized. Furthermore a neuronal receptor complex and several intracellular substrates leading to outgrowth inhibition have been identified. Rapid progress has also been made in identifying the role of neurotrophins and other positive cues in promoting axonal regrowth. The most recent advances in our understanding of positive stimuli for axon regeneration come from transplantation studies at the CNS lesion site. A number of artificial substrates, tissues, and cells including fetal cells, neural stem cells, Schwann cells and olfactory-ensheathing cells have been tested in animal models of CNS injury. Based on our expanded knowledge of inhibitory influences and on the positive characteristics of various transplants, a number of interventions have been tested to promote recovery in models of CNS trauma. These advances represent the first steps in developing a viable therapy to promote axon regeneration following CNS trauma.     

Factors influencing the regeneration of axons in the central nervous system

Damage to the central nervous system (CNS) causes damage to neurons. This damage can result in the complete death of neurons, or in them becoming disconnected from their inputs or target structures due to disruption of axons. The main reason why damage to the human CNS is so disastrous and disabling is that axons will not in general regenerate in the mammalian brain, and neurons once lost are not replaced. In order, therefore, to repair the CNS, techniques will have to be developed to replace dead neurons, and induce axon regrowth. Central to the technologies necessary for brain repair is the ability to induce and control the growth of axons, since in a damaged brain both surviving and newly implanted neurons must grow axons to make or remake appropriate synaptic connections. Worthwhile treatments, however, do not necessarily require the repair of all the damaged circuits in the CNS, it may be possible to substantially improve the function of patients with relatively few reconnected axons, if those axons are ones which mediate particularly important behaviours, such as respiration, bladder control, or hand and arm movements.     

Self-healing hydrogel for tissue repair in the central nervous system

<正>Neurological disorders are diseases of the central and peripheral nervous systems.These disorders include Alzheimer’s disease,epilepsy,brain tumor,and cerebrovascular diseases(stroke,migraine and other headache disorders,multiple sclerosis,Parkinson’s disease,and neuroinfections).Hundreds of millions     

Widespread regeneration of central axons through the central nervous system of the goldfish

The ability of neurons in the brain of the goldfish to regenerate their axons was examined using anterograde and retrograde axonal tracing methods. It was found that all neurons in the thalamus and brainstem that project to the optic tectum can regenerate their axons after removal of the tectal lobe, and that their axons can often grow for considerably greater distances than they normally extend. In addition, they can penetrate (and, presumably, innervate) their normal target tissue, even if it is displaced into an ectopic location.     

Neurotrophic effect of hepatocyte growth factor on central nervous system neurons in vitro

Although the expression of hepatocyte growth factor (HGF) and its receptor, proto-oncogene c-met, has been demonstrated in the central nervous system (CNS), the function of HGF in the CNS was not fully understood. In the present studies, we determined the effects of HGF on neuronal development in neocortical explant and mesencephalic neurons obtained from embryonic rat brain. HGF clearly enhanced neurite outgrowth in neocortical explants. In the mesencephalic culture, the number of tyrosine hydroxylase (TH)-positive neurons was significantly higher in the HGF-treated wells and the neurites of the TH-positive neurons appear to be more developed. Moreover, the dopamine uptake into mesencephalic neurons was also enhanced by HGF treatment, indicating that HGF promotes the survival and/or maturation of mesencephalic dopaminergic neurons. In both neocortical explants and mesencephalic neurons, c-met autophosphorylation was induced by HGF and MAP kinase activation was also detected in the neocortical explant. Furthermore, Western blot analysis of the cultured CNS cells revealed that HGF was expressed mainly in microglia. These results suggest that HGF from microglia has neurotrophic activity on the CNS neurons and plays significant roles in the development of the CNS. © 1996 Wiley-Liss, Inc.     

Strategies for axonal repair in central nervous system diseases

Journal of Neurology - Significant functional recovery after spinal cord injury can be observed in rodents, in spite of the presence of extensive irreversible structural damage. One potential...