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PubMed2003

c-Jun expression in surviving and regenerating retinal ganglion cells: effects of intravitreal neurotrophic supply.

PURPOSE: To investigate c-jun expression in surviving and axon-regenerating retinal ganglion cells (RGCs) and the effect of intravitreal neurotrophic supply on c-jun expression. METHODS: All animals underwent optic nerve transection (ONT) 0.5 mm behind the eyeball. Some animals underwent a replacement of the optic nerve with an autologous sciatic nerve graft (SNG) to allow axonal regrowth. To provide a neurotrophic supply, a peripheral nerve (PN) segment or brain-derived neurotrophic factor (BDNF)/ciliary neurotrophic factor (CNTF) was applied intravitreally. The time course of c-jun expression was first examined in both surviving and regenerating RGCs. Then, c-jun expression was examined in surviving and regenerating RGCs 3 weeks after intravitreal BDNF/CNTF treatment. Animals with vehicle eye injection were used as the control. Fluorescent dye was used for retrograde labeling of surviving (applied behind the eyeball) and regenerating (applied at the distal end of the SNG) RGCs. All retinas were immunohistochemically stained for c-jun. RESULTS: c-Jun was not detected in normal RGCs, but weak expression was seen in surviving RGCs after ON injury. The proportion of c-jun-positive (+) RGCs among surviving cell population was 52.6% to 86.5% 2 to 6 weeks after ONT. Among regenerating RGCs, more than 80% expressed c-jun in all treatment groups, a proportion that was significantly higher after CNTF treatment (90.7%). In addition, c-jun expression was much stronger in intensity and the c-jun(+) nuclei were much larger in regenerating than in surviving RGCs. CONCLUSIONS: c-Jun expression in RGCs was upregulated after injury. Most regenerating RGCs were c-jun(+), and the intensity of c-jun expression was higher in regenerating than in surviving RGCs. CNTF also upregulated c-jun expression in RGCs.

Animals↗
PubMed2000

Morphological and functional study of regenerated chorda tympani nerves in humans.

It is still unclear whether the chorda tympani nerves in humans regenerate after being severed during middle ear surgery, although functional studies have demonstrated recovery of taste 1 to 2 years after surgery. To date, 12 cases of regenerated chorda tympani nerves have been found in our series of patients during secondary surgery. The regenerated nerves of 3 cases of the 12 were removed as samples during secondary surgery to detect regenerated myelinated axons. All regenerated nerves were in the submucosal connective tissue layer of the reconstructed eardrum. In the regenerated nerves, myelinated nerve fibers existed in a small fascicle or in connective tissue, but the number of myelinated axons was low compared with that in normal subjects ( 1.752 +/- 78; n = 3), and the distribution was sparse. The total number of regenerated myelinated axons varied from 141 (8.3%) to 979 (55.9%). From a functional study using electrogustometry, incomplete recovery of electrogustation was observed in all 3 cases before secondary surgery, suggesting that chorda tympani nerves actually regenerate in the middle ear and do function.

Adult↗
PubMed1984

Glial fibrillary acidic protein in regenerating teleost spinal cord.

Immunohistological and ultrastructural studies were carried out on normal and regenerating spinal cord of the gymnotid Sternarchus albifrons, and in the brain and spinal cord of the goldfish Carassius auratus, to examine the distribution of glial fibrillary acidic protein (GFAP) in these tissues. Sections of normal goldfish brain and spinal cord exhibited positive staining for GFAP. In normal Sternarchus spinal cord, electron microscopy has revealed filament-filled astrocytic processes; however, such astrocytic profiles were more numerous in regenerated cord. Likewise, while normal Sternarchus spinal cord showed only a small amount of GFAP staining, regenerated cords were strongly positive for GFAP. Positive staining with anti-GFAP was observed along the entire length of the regenerated cord in Sternarchus, and was especially strong in the transition zone between regenerated and unregenerated cord. Both regeneration of neurites and production of new neuronal cell bodies occur readily in such regenerating Sternarchus spinal cords (Anderson MJ, Waxman SG: J Hirnforsch 24: 371, 1983). These results demonstrate that the presence of GFAP and reactive astrocytes in Sternarchus spinal cord does not prevent neuronal regeneration in this species.

Animals↗
PubMed2005

Muscle regeneration in dystrophin-deficient mdx mice studied by gene expression profiling.

BACKGROUND: Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is lethal. In contrast, dystrophin-deficient mdx mice recover due to effective regeneration of affected muscle tissue. To characterize the molecular processes associated with regeneration, we compared gene expression levels in hindlimb muscle tissue of mdx and control mice at 9 timepoints, ranging from 1-20 weeks of age. RESULTS: Out of 7776 genes, 1735 were differentially expressed between mdx and control muscle at at least one timepoint (p < 0.05 after Bonferroni correction). We found that genes coding for components of the dystrophin-associated glycoprotein complex are generally downregulated in the mdx mouse. Based on functional characteristics such as membrane localization, signal transduction, and transcriptional activation, 166 differentially expressed genes with possible functions in regeneration were analyzed in more detail. The majority of these genes peak at the age of 8 weeks, where the regeneration activity is maximal. The following pathways are activated, as shown by upregulation of multiple members per signalling pathway: the Notch-Delta pathway that plays a role in the activation of satellite cells, and the Bmp15 and Neuregulin 3 signalling pathways that may regulate proliferation and differentiation of satellite cells. In DMD patients, only few of the identified regeneration-associated genes were found activated, indicating less efficient regeneration processes in humans. CONCLUSION: Based on the observed expression profiles, we describe a model for muscle regeneration in mdx mice, which may provide new leads for development of DMD therapies based on the improvement of muscle regeneration efficacy.

Adolescent↗
PubMed2004

Cell lineage tracing during Xenopus tail regeneration.

The tail of the Xenopus tadpole will regenerate following amputation, and all three of the main axial structures - the spinal cord, the notochord and the segmented myotomes - are found in the regenerated tail. We have investigated the cellular origin of each of these three tissue types during regeneration. We produced Xenopus laevis embryos transgenic for the CMV (Simian Cytomegalovirus) promoter driving GFP (Green Fluorescent Protein) ubiquitously throughout the embryo. Single tissues were then specifically labelled by making grafts at the neurula stage from transgenic donors to unlabelled hosts. When the hosts have developed to tadpoles, they carry a region of the appropriate tissue labelled with GFP. These tails were amputated through the labelled region and the distribution of labelled cells in the regenerate was followed. We also labelled myofibres using the Cre-lox method. The results show that the spinal cord and the notochord regenerate from the same tissue type in the stump, with no labelling of other tissues. In the case of the muscle, we show that the myofibres of the regenerate arise from satellite cells and not from the pre-existing myofibres. This shows that metaplasia between differentiated cell types does not occur, and that the process of Xenopus tail regeneration is more akin to tissue renewal in mammals than to urodele tail regeneration.

Actins↗
PubMed1996

Appropriate pattern formation following regulative regeneration in the hindbrain neural tube.

Patterns of neuronal differentiation and axon outgrowth were examined in regenerated neural tissue of the hindbrain of the chicken embryo. Specific regions of the hindbrain neural tube corresponding to identified rhombomeres were selectively removed unilaterally by microsurgery. Of the embryos that survived, about 35% exhibited regulative regeneration, wherein the missing hemi-rhombomere was reconstituted to normal size and morphology through compensatory proliferation and migration from adjacent tissue. The capacity for regeneration depended on the embryonic stage at which the ablation was performed and on whether the midline floor plate was included in the ablation. Ablations performed prior to the formation of morphologically overt rhombomere boundaries led to significantly lower frequencies of regulative regeneration than ablations performed after the formation of boundaries. Ablations that included the floor plate led to significantly lower frequencies of regulative regeneration than ablations sparing the floor plate. Regulative regeneration was also observed at low frequency following excision of an entire rhombomere. Within the regenerated hemi-rhombomere, identified neuron groups appeared in their normal positions and differentiated normal patterns of migration and axon outgrowth. The fidelity of this patterning, however, depended on the mediolateral position of the neuron group, being more reliable for neuron groups in the basal plate than in the alar plate. These results confirm the extensive regulative potential of the neural tube and demonstrate the capacity for appropriately patterned cellular differentiation within the regenerated tissue.

Animals↗
PubMed1987

Dorsal root ganglia grafts stimulate regeneration of denervated urodele forelimbs: timing of graft implantation with respect to denervation.

Amphibian forelimb regeneration is a nerve-dependent process; nerves presumably release one or more neurotrophic factors that stimulate blastema cell division. To date several candidate molecules/factors have been shown to stimulate macromolecular synthesis and/or mitosis but sustained cell cycle activity and blastema development have not been achieved. Because dorsal root ganglia (DRG) implants are capable of promoting regeneration of denervated adult newt limbs (Kamrin & Singer, 1959), we have evaluated the DRG stimulation of regeneration in denervated limbs of adult newts and larval axolotls; two alternative timing strategies were tested as a step toward defining bioassay parameters that best reflect neurotrophic activity. The frequency of regeneration in denervated adult newt limbs was compared after providing DRG before or at the time of denervation (to maintain neurotrophic and cell cycle activity) versus DRG implantation at various postdenervation times (to resupply neurotrophic activity and restimulate suppressed cell cycle activity). The results show that denervated adult newt limbs regenerated most frequently using the maintenance strategy, but as the denervation interval was extended in the restimulation strategy, the frequency of regeneration declined. Larval axolotl limbs responded positively in both maintenance and restimulation DRG-grafting protocols. These results suggest that the efficacy of DRG stimulation of regeneration in adult newts was related to the relative number of blastema cells present at the time of denervation and the proliferative status of the blastema cells; bioassays with denervated adult newt limbs should be designed with these constraints in mind. Because such constraints are not as problematic with the larval axolotl, this species may provide the best opportunity for further defining bioassay parameters related to the neurotrophic stimulation of regeneration.

Animals↗
PubMed1987

Tinkering with successful synapse regeneration in the leech: adding insult to injury.

In the leech, synapse regeneration in adults and synapse formation during embryonic development can be studied in single, identifiable cells that make precise connections with their targets. Certain cellular components, such as synaptic targets and glia, were selectively destroyed to study how the regenerating axons locate their targets, what triggers axons to start growing and what stops them. The results showed that glia and targets play only a limited role in synapse regeneration and in axon degeneration. For example, contact with the synaptic target may inhibit sprouting and availability of targets may promote it. Comparative studies on axon growth and synapse formation by interneurones in embryos showed that regeneration does not simply recapitulate embryonic development. There are clearly separate constraints on the two processes. Axon survival is a different problem. Although isolated axon segments can survive for up to a year in the leech, temperature is a major factor in survival. Axon segments in a tropical leech that regenerates synapses well at 31 degrees C degenerated within 2-3 weeks at this elevated temperature, even when regeneration was prevented. In similar leeches at room temperature (22 degrees C), segments survived for months. Overall, results in the leech support the idea that degeneration as well as regeneration share fundamental mechanisms with other invertebrates and the vertebrates, including mammals. Perhaps long-lived axon segments and other features of the leech that speed or encourage functional regeneration can now be made to operate in repair of the mammalian nervous system.

Animals↗
PubMed2006

Disruption of the middle hepatic vein is not crucial for liver regeneration of the remnant liver after right hemihepatectomy for hepatic tumors.

BACKGROUND: To clarify the role of the middle hepatic vein (MHV) in liver regeneration of the remnant liver after right hemihepatectomy for hepatic tumors, we reviewed 29 patients to evaluate liver regeneration for up to 12 postoperative months. METHODS: Volume regeneration of the remnant liver was investigated by computed tomography at 3, 6, and 12 postoperative months. The remnant liver was divided into the following three areas: the medial section (segment IV), the lateral section (segments II and III), and segment I. The patients were divided into two groups: group A (n = 17), in which the MHV was preserved in the remnant liver, and group B (n = 12), in which the MHV was removed. RESULTS: Volume regeneration of each area continued until 6 postoperative months but did not increase thereafter. On univariate analysis, differences in the volume regeneration of each area between the groups were not significant at any measured time point. Furthermore, disruption of the MHV was determined to not be crucial to the volume regeneration of any liver area on multivariate analysis. Only the resection volume (percentage) significantly affected liver regeneration of the remnant liver. CONCLUSIONS: Disruption of the MHV does not decisively affect liver regeneration of remnant liver after right hemihepatectomy for hepatic tumors.

Female↗
PubMed2004

Axonal regeneration of fish optic nerve after injury.

Since Sperry's work in the 1950s, it has been known that the central nervous system (CNS) neurons of lower vertebrates such as fish and amphibians can regenerate after axotomy, whereas the CNS neurons of mammals become apoptotic after axotomy. The goldfish optic nerve (ON) is one of the most studied animal models of CNS regeneration. Morphological changes in the goldfish retina and tectum after ON transection were first researched in the 1970s-1980s. Many biochemical studies of neurite outgrowth-promoting substances were then carried out in the 1980s-1990s. Many factors have been reported to be active substances that show increased levels during fish ON regeneration, as shown by using various protein chemistry techniques. However, there are very few molecular cloning techniques for studying ON regeneration after injury. In this review article, we summarize the neurite outgrowth-promoting factors reported by other researchers and describe our strategies for searching for ON regenerating molecules using a differential hybridization technique in the goldfish visual system. The process of goldfish ON regeneration after injury is very long. It takes about half a year from the start of axonal regrowth to complete restoration of vision. The process has been classified into three stages: early, middle and late. We screened for genes with increased expression during regeneration using axotomized goldfish retinal and tectal cDNA libraries and obtained stage-specific cDNA clones that were upregulated in the retina and tectum. We further discuss functional roles of these molecules in the regeneration processes of goldfish ON.

Animals↗
PubMed2006

Involvement of Cdc2 in axonal regeneration enhanced by exercise training in rats.

PURPOSE: Physical activity can improve sensorimotor recovery after peripheral nerve injury. We examined the effects of treadmill training (TMT) on axonal regeneration in the injured sciatic nerve of the rat and further investigated cellular and molecular events that underlie enhanced axonal regrowth by training. METHODS: After crush injury of the sciatic nerves, rats were randomly assigned into either TMT or sedentary groups. Three to 14 d after injury, changes in protein levels in the regenerating nerve were analyzed by Western blotting and immunofluorescence staining. Axonal regeneration was assessed by anterograde and retrograde tracing techniques. The animals' functional recovery was determined by the sciatic functional index. RESULTS: We identified enhanced axonal regrowth in the distal stump of the sciatic nerve 7-14 d after injury in the rats with TMT. Cell division cycle 2 (Cdc2) mRNA and protein levels were highly increased in the injured sciatic nerves 3 and 7 d after injury, and decreased to basal levels 14 d later. Daily TMT accelerated distal shift of Cdc2 mRNA and protein induced in the regenerating nerves, and Cdc2 kinase activity was similarly increased in the distal stump by TMT. Cdc2 protein induced by TMT was mainly colocalized with Schwann cell marker S100beta protein, and correlated with axial distribution pattern of bromodeoxyuridine-labeled proliferating cell population in the regenerating nerve. We further demonstrate that axonal regeneration and motor function recovery after injury, both of which were promoted by TMT, were greatly suppressed by in vivo administration of Cdc2 inhibitor roscovitine. CONCLUSION: The present data suggest that Cdc2 kinase activated in the regenerating sciatic nerve may play an important role in TMT-mediated enhancement of axonal regeneration.

Animals↗
PubMed1993

Rabbit facial nerve regeneration in NGF-containing silastic tubes.

Previous reports suggest that exogenous nerve growth factor (NGF) enhanced nerve regeneration in rabbit facial nerves. Rabbit facial nerve regeneration in 10-mm Silastic tubes prefilled with NGF was compared to cytochrome C (Cyt. C), bridging an 8-mm nerve gap. Three weeks following implantation, NGF-treated regenerates exhibited a more mature fascicular organization and more extensive neovascularization than cytochrome-C-treated controls. Morphometric analysis at the midtube of 3- and 5-week regenerates revealed no significant difference in the mean number of myelinated or unmyelinated axons between NGF- and cytochrome-C-treated implants. However, when the number of myelinated fibers in 5-week regenerates were compared to their respective preoperative controls, NGF-treated regenerates had recovered a significantly greater percentage of myelinated axons than cytochrome-C--treated implants (46% vs. 18%, respectively). In addition, NGF-containing chambers reinnervated a higher percentage of myelinated axons in the distal transected neural stumps (49% vs. 34%). Behavioral and electrophysiologic studies demonstrated spontaneous and induced activities in the target muscles when approximately one third of the myelinated axons were recovered in the midchamber (1280 axons). Horseradish peroxidase (HRP) studies demonstrated retrograde axonal transport to the midchamber and proximal transected neural stump. PC12 bioassay demonstrated persistent NGF activity in the intrachamber fluids at 3 (5:1 dilution) and 5 (2:1 dilution) weeks of entubation. Electrophysiologic tests demonstrated a slow conduction velocity of a propagated electrical impulse (43.5 m/s-1 vs. 67 m/s-1) and shallow wide compound action potential. In wider defects (15-mm chambers) and longer entubation periods (7 weeks), no regeneration or NGF activity was seen. Therefore, exogenous NGF provides an early but limited neurotrophic effect on the regeneration of the rabbit buccal division of the facial nerve and a limited behavioral and physiological improvement in the target muscles.

Animals↗
PubMed2005

Polysialylated neural cell adhesion molecule is necessary for selective targeting of regenerating motor neurons.

It is well established that peripheral nerves regenerate after injury. Therefore, incomplete functional recovery usually results from misguided axons rather than a lack of regeneration per se. Despite this knowledge very little is known about the molecular mechanisms regulating axon guidance during regeneration. In the developing neuromuscular system the neural cell adhesion molecule (NCAM) and its polysialic acid (PSA) moiety are essential for proper motor axon guidance. In this study we used a well established model of nerve transection and repair to examine whether NCAM and/or PSA promotes selective regeneration of femoral motor nerves in wild-type and NCAM (-/-) mice. We found that regenerating axons innervating the muscle pathway and, to a lesser extent, cutaneous axons in the sensory pathway reexpress high levels of PSA during the time when the cut axons are crossing the lesion site. Second, we found that motor neurons in wild-type mice preferentially reinnervated muscle pathways, whereas motor neurons in NCAM (-/-) mice reinnervated muscle and cutaneous pathways with equal preference. Preferential regeneration was not observed in wild-type mice when PSA was removed enzymatically from the regenerating nerve, indicating that this form of selective motor axon targeting requires PSA. Finally, transgenic mice were used to show that the number of collateral sprouts, their field of arborization, and the withdrawal of misprojected axons were all attenuated significantly in mice lacking PSA. These results indicate that regenerating motor axons must express polysialylated NCAM, which reduces axon-axon adhesion and enables motor neurons to reinnervate their appropriate muscle targets selectively.

Animals↗
PubMed2002

Impaired regeneration of dystrophin-deficient muscle fibers is caused by exhaustion of myogenic cells.

Duchenne muscular dystrophy is one of the most devastating myopathies. Muscle fibers undergo necrosis and lose their ability to regenerate, and this may be related to increased interstitial fibrosis or the exhaustion of satellite cells. In this study, we used mdx mice, an animal model of Duchenne muscular dystrophy, to assess whether muscle fibers lose their ability to regenerate after repeated cycles of degeneration-regeneration and to establish the role of interstitial fibrosis or exhaustion of satellite cells in this process. Repeated degenerative-regenerative cycles were induced by the injection of bupivacaine (33 mg/kg), a myotoxic agent. Bupivacaine was injected weekly into the right tibialis anterior muscle of male, 8-week-old mdx (N = 20) and C57Bl/10 (control, N = 10) mice for 20 and 50 weeks. Three weeks after the last injection, the mice were killed and the proportion of regenerated fibers was counted and reported as a fibrosis index. Twenty weekly bupivacaine injections did not change the ability of mdx muscle to regenerate. However, after 50 weekly bupivacaine injections, there was a significant decrease in the regenerative response. There was no correlation between the inability to regenerate and the increase in interstitial fibrosis. These results show that after prolonged repeated cycles of degeneration-regeneration, mdx muscle loses its ability to regenerate because of the exhaustion of satellite cells, rather than because of an increase in interstitial fibrosis. This finding may be relevant to cell and gene therapy in the treatment of Duchenne muscular dystrophy.

Anesthetics, Local↗
PubMed1999

The role of Kupffer cells in liver regeneration.

The liver has a remarkable proliferative capacity after a partial hepatectomy. Previous studies have indicated that Kupffer cells have the potential to exert both stimulatory and inhibitory influences on hepatocyte proliferation. To elucidate the role of Kupffer cells in liver regeneration, mice were selectively depleted of Kupffer cells by injection of liposome-encapsulated dichloromethylene diphosphonate (lipo-MDP) at day 3 after a two-thirds hepatectomy. Results showed that liver regeneration was delayed after Kupffer cell-depletion. In control mice, hepatocyte growth factor (HGF) mRNA expressions were enhanced during liver regeneration and expressions of HGF were localized in fat-storing cells (Ito cells). In Kupffer cell-depleted mice, the number of HGF-expressing cells decreased in the regenerating liver, and expressions of HGF and its receptor (c-met) as well as other growth factors/cytokines were less prominent than in control mice. In contrast, expressions of TNF-alpha, another potent cytokine involved in liver regeneration, did not differ between Kupffer cell-depleted and control mice during the regeneration. Administration of TNF-alpha antibody did not reduce the expression of HGF or liver regeneration. These findings imply that Kupffer cells play a stimulatory role in liver regeneration by enhancing HGF expression via TNF-alpha-non-mediated mechanisms.

Animals↗
PubMed2000

Morphological and cytochemical characteristics of periodontal Ruffini ending under normal and regeneration processes.

Current knowledge on the Ruffini endings, primary mechanoreceptors in the periodontal ligament is reviewed with special reference to their cytochemical features and regeneration process. Morphologically, they are characterized by extensive ramifications of expanded axonal terminals and an association with specialized Schwann cells, called lamellar or terminal Schwann cells, which are categorized, based on their histochemical properties, as non-myelin-forming Schwann cells. Following nerve injury, the periodontal Ruffini endings of the rat incisor ligament can regenerate more rapidly than Ruffini endings in other tissues. During regeneration, terminal Schwann cells associated with the periodontal Ruffini endings migrate into regions where they are never found under normal conditions. Also during regeneration, alterations in the expression level of various bioactive substances occur in both axonal and Schwann cell elements in the periodontal Ruffini endings. Neuropeptide Y, which is not detected in intact periodontal Ruffini endings, is transiently expressed in their regenerating axons. Growth-associated protein-43 (GAP-43) is expressed transiently in both axonal and Schwann cell elements during regeneration, while this protein is localized in the Schwann sheath of periodontal Ruffini endings under normal conditions. The expression of calbindin D28k and calretinin, both belonging to the buffering type of calcium-binding proteins, was delayed in periodontal Ruffini endings, compared to their morphological regeneration. As the importance of axon-Schwann cell interactions has been proposed, further investigations are needed to elucidate their molecular mechanism particularly the contribution of growth factors during the regeneration as well as development of the periodontal Ruffini endings.

Animals↗
PubMed1996

Peripheral nerve regeneration in a silicone tube: effect of collagen sponge prosthesis, laminin, and pyrimidine compound administration.

Regeneration of transected peripheral nerve with a 10-mm gap encased in a silicone tube was evaluated in the presence of collagen sponge with or without laminin, or with systemic administration of a pyrimidine compound, MS-818. The sciatic nerve of 20 adult rats was transected and the proximal and distal nerve stumps were fixed in a silicone tube. The lumen of the silicone tube was empty, or filled with a collagen sponge alone or with a laminin-soaked collagen sponge. Also, a pyrimidine compound was injected intraperitoneally after implantation of the empty silicone tube. Three weeks later, the contents of the silicone tubes were processed for histological examination of regenerated nerve fibers. Other animals were observed 6, 12, and 18 months after surgery to examine the long-term effects of the collagen sponge on nerve regeneration. All animals had regenerated tissue within the tube 3 weeks after nerve transection. The diameter of the tissue decreased toward the distal stump in the empty tube, but was the same throughout the full length in the collagen sponge-containing tube. Immunohistochemical studies revealed that the nerve fibers extended beyond the midline of the regenerated tissue in animals treated with a laminin-containing collagen sponge or receiving a pyrimidine compound. Long-term observation showed the regenerated nerve was thick as the proximal stump and many neurofilament- and peripheral myelin-positive fibers were observed around the collagen sponge. Collagen sponge assists the progress of regenerated tissues in silicone tubes, and laminin-containing prostheses and administration of a pyrimidine compound enhance peripheral nerve regeneration.

Animals↗
PubMed1987

Molecular and cellular aspects of nerve regeneration.

Injury of an axon leads to at least four independent events, summarized in Figure 1: first, deprivation of the nerve cell body from target-derived or mediated substances, which leads to a derepressed or a permissive state; second, disruption of anterograde transport, with a resultant accumulation of anterogradely transported molecules; third, environmental response with possible consequent changes in constituents of the extracellular matrix and substances secreted from the surrounding cells; and fourth, appearance of growth inhibitors and modified protease activity. It seems that the first three of these events are obligatory, but not sufficient, i.e., they lead to a growth state only if the cell body is able to respond to the injury-induced signals from the environment (a and b). The regenerative state is characterized by alterations in protein synthesis and axonal transport and by sprouting activity. The subsequent elongation of the growing fibers depends on a continuous supply of appropriate growth factors. These factors are presumably anchored to the appropriate extracellular matrix that serves as a substratum for elongating fibers. It should be mentioned that the proliferating nonneuronal cells have a conducive effect on regeneration by forming a scaffold for the growing fibers. Accordingly, the lack of regeneration may stem from a deficiency in the ability of glial cells to provide the appropriate soluble components or from insufficient formation of extracellular matrix. In this respect, one may consider regeneration of an injured axon as a process which involves regeneration of both the nonneuronal cells and the supported axons. The regeneration of glial cells may fulfill the rules which are applied to regeneration of any other proliferating tissue. Furthermore, the processes of regeneration in the axon and the glial cells are mutually dependent. Perhaps the triggering factors provided by the nonneuronal cells affect the nonneuronal cells themselves by modulating their postlesion gliosis and thereby inducing their appropriate activation. In such a case, regeneration of nonneuronal cells may resemble an autocrine type of regulation that exists also during ontogeny. The growth regulation is shifted back to the paracrine type upon neuronal maturation or cessation of axonal growth. When the elongating fibers reach the vicinity of the target organ, they are under the influence of the target-derived factors, which guide the fibers and eventually cease their elongation.

Animals↗