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PubMed1996

The expression of nerve growth factor receptor on Schwann cells and the effect of these cells on the regeneration of axons in traumatically injured human spinal cord.

To investigate the effects of Schwann cells and nerve growth factor receptor (NGFR) on the regeneration of axons, autopsy specimens of spinal cord from 21 patients with a survival time of 2 h to 54 years after spinal cord trauma were studied using immunohistochemistry and electron microscopy. Regenerating sprouts of axons could be observed as early as 4 days after trauma. At 4.5 months after trauma, many regenerating nests of axons appeared in the injured spinal cord. The regeneration nests contained directionally arranged axons and Schwann cells. Some axons were myelinated. In injured levels of the spinal cord, the Schwann cells exhibited an increased expression of NGFR within spinal roots. These results show that an active regeneration process occurs in traumatically injured human spinal cord. The NGFR expressed on Schwann cells could mediate NGF to support and induce the axon regeneration in the central nervous system.

Adolescent↗

PubMed2000

Expression of MyoD and myogenin in dystrophic mice, mdx and dy, during regeneration.

Expression of two myogenic regulatory factors, MyoD and myogenin, was studied in regenerating muscles of dystrophic mice and compared to a chemically induced regeneration process. First, the distribution of the two proteins was determined immunohistochemically at various time points after single administrations of a local anaesthetic, bupivacaine hydrochloride, which causes myonecrosis followed by regeneration. Detectable levels of MyoD appeared at 18 h and the expression reached their maximum levels at 48 h after the injection, which coincide with the stage when satellite cells are activated and start to proliferate. Myogenin became detectable in 24 h and its expression reached its highest level at 72 h after injection when newly formed myotubes appeared. The two genes were also expressed in the dystrophic muscles from dy and mdx mice which exhibit dystrophic pathological features but are associated with different phenotypes. In mdx mice the two genes were expressed at reasonably high levels in parallel with the active regenerating process, whereas in dy mice MyoD and myogenin expressions decreased as fibrosis progressed. However, MyoD was relatively more strongly expressed in the larger mature myotubes of dy mice than in those of mdx mice, suggesting prolonged regenerative activity. In dy and mdx mice, MyoD and myogenin were expressed in different quantities, indicating that these animals have distinct regenerating activities. Our findings confirm that expression of both MyoD and myogenin genes is necessary in the regenerative process for the proliferation of satellite cells (myoblasts) and for the development of early regenerating fibers (myotubes) even in dystrophic muscles.

Animals↗

PubMed1997

Effect of increased physical activity on growth and differentiation of regenerating rat soleus muscle.

Our purpose was to determine the effect of physical exercise on growth and differentiation during regeneration of a slow-twitch muscle. Degeneration/regeneration of the left soleus muscles of Wistar female rats was induced by injection of a snake venom. Muscular differentiation was studied by monitoring the sequential expression of the various myosin heavy chain isoforms (MHCs). Rats were assigned to one of two groups: cage sedentary (n = 14) or exercised (n = 16). The exercise programme began 1-day post-injection and the rats ran 1 h/day on a motorized treadmill. Then, 9 and 25 days after venom treatment, the soleus MHC phenotype as determined by immunohistology, electrophoresis and immunoblotting, was studied. At 25 days the expression of MHCs by regenerating soleus was not changed by the increased level of physical activity (P > 0.05). Exercised and sedentary regenerating muscles contained similar numbers of type-I fibres (100% of total fibres), levels of MHC-1 (85.4 and 89.5% of total MHCs), MHC-2a and M/HC-2x/d and their fibres expressed MHC-1 (100% of total fibres) and MHC-2 (45-50%) in the same way. Moreover, the masses of regenerating and nonregenerating soleus were significantly increased by physical exercise (P < 0.02). At 9 days no effect of muscular exercise was found. In conclusion, endurance exercise did not alter differentiation of regenerating soleus. Moreover regenerating soleus can respond to increased physical activity by enhancing its mass in the same way as mature muscle.

Animals↗

PubMed2005

Afuni, a novel transforming growth factor-beta gene is involved in arm regeneration by the brittle star Amphiura filiformis.

The bone morphogenetic proteins (BMPs) are a family of the transforming growth factor-beta (TGF-beta) superfamily that perform multiple roles during vertebrate and invertebrate development. Here, we report the molecular cloning of a novel BMP from regenerating arms of the ophiuroid Amphiura filiformis. The theoretically translated amino acid sequence of this novel BMP has high similarity to that of the sea urchin BMP univin. This novel BMP has been named afuni. Whole-mount in situ hybridisation implicates afuni in arm regeneration. Expression occurs in distinct proximal and distal regions of late regenerates (3- and 5-week postablation). These sites are at different stages of regeneration, suggesting multiple roles for this gene in adult arm development. Cellular expression of this gene occurs in migratory cells within the radial water canal (RWC) of regenerating and nonregenerating arms. These migrating coelomocytes suggest a key role for the coelomic RWC as a source of the cellular material for use in arm regeneration by A. filiformis.

Amino Acid Sequence↗

PubMed2000

Nervous system dynamics during fragmentation and regeneration in Enchytraeus japonensis (Oligochaeta, Annelida).

Enchytraeus japonensis is a small terrestrial oligochaete which primarily reproduces asexually by fragmentation and regeneration. In order to introduce a molecular approach to the study of regeneration we developed a whole-mount immunostaining procedure for the worm. Using an antibody directed against acetylated tubulin in conjunction with confocal laser-scanning microscopy, we succeeded in clarifying the three- dimensional structure of the entire nervous system in the full-grown worm and its dynamics during the fragmentation and regeneration process. In addition, we examined the expression of neurotransmitters and neuropeptides in the worm using a fluorescently-labeled antagonist and various antibodies. In particular, we found two circumferential structures in the body wall muscle of each segment that react strongly with alpha-bungarotoxin, an antagonist of nicotinic acetylcholine receptors, and detected nerve fibers just underneath these structures. During the fragmentation process, the circular body wall muscles contract near one of these circumferential structures in the middle of the segment, which causes constriction and results in fission of the body. This alpha-bungarotoxin-positive structure was designated the neuromuscular junction of the circular muscle. During the regeneration process nerve fibers grow from the remaining ventral nerve cord and gradually form networks in both the anterior and posterior regeneration buds. The growing fibers extend to the prostomium (a sensory organ) at the anterior end prior to connecting to the presumptive brain rudiment. A neural network appears around the pygidium, and this is followed by growth of the body at the posterior end. The nervous system appears to play an important role in both anterior and posterior regeneration.

Animals↗

PubMed2006

Contribution of mesenterial muscle dedifferentiation to intestine regeneration in the sea cucumber Holothuria glaberrima.

Holothurians (sea cucumbers) have been known from ancient times to have the capacity to regenerate their internal organs. In the species Holothuria glaberrima, intestinal regeneration involves the formation of thickenings along the free mesentery edge; these thickenings will later give rise to the regenerated organ. We have previously documented that a remodeling of the extracellular matrix and changes in the muscle layer occur during the formation of the intestinal primordium. In order to analyze these changes in depth, we have now used immunocytochemical techniques and transmission electron microscopy. Our results show a striking disorganization of the muscle layer together with myocyte dedifferentiation. This dedifferentiation involves nucleic activation, disruptions of intercellular junctions, and the disappearance of cell projections, but more prominently, the loss of the contractile apparatus by the formation and elimination of spindle-like structures. Muscle dedifferentiation can be seen as early as 2 days following evisceration and continues during the next 2 weeks of the regeneration process. Dedifferentiation of myocytes might result in cells that proliferate and give rise to new myocytes. Alternatively, dedifferentiating myocytes could give rise to cells with high nuclear-to-cytoplasmic ratios, with some being eliminated by apoptosis. Our results, together with those in other regeneration models, show that myocyte dedifferentiation is a common event in regeneration processes and that the dedifferentiated cells might play an important role in the formation of the new tissues or organs.

Animals↗

PubMed1999

The Reg gene family and Reg proteins: with special attention to the regeneration of pancreatic beta-cells.

Pancreatic beta-cells of the islets of Langerhans are the only cells that produce insulin in humans, as well as in most animals, but they have been thought to have a limited capacity for regeneration, which is a predisposing factor for the development of diabetes mellitus. Strategies for influencing the replication and growth of the beta-cell mass are therefore important for the prevention and/or treatment of diabetes. We have established a model for islet regeneration in 90% depancreatized rats by the administration of poly(ADP-ribose) synthetase inhibitors such as nicotinamide. The regenerating islets in the remaining pancreas of poly(ADP-ribose) synthetase inhibitor-treated rats were markedly enlarged and consisted largely of insulin-producing beta-cells, preventing the development of diabetes mellitus that would otherwise be caused by the 90% pancreatectomy. In screening the regenerating islet-derived cDNA library, we found a novel gene and named it Reg (i.e., regenerating gene). The rate Reg cDNA had a single open reading frame that encoded a 165-amino acid protein with a 21-amino acid signal peptide. We also isolated the human REG cDNA which encoded a 166-amino acid protein with a 22-amino acid signal peptide. The amino acid sequence of human REG protein has 68% homology to that of rat Reg protein. Recombinant rat Reg protein without the signal peptide, produced in yeast, stimulated beta-cell replication and increased the beta-cell mass in the residual pancreas of 90% depancreatized rats, ameliorating the surgical diabetes. Recombinant human REG protein also induced an expansion of the beta-cell mass in non-obese diabetic (NOD) mice, resulting in the amelioration of diabetes. These results, as well as several other lines of evidence, indicate that Reg protein is a growth factor for pancreatic beta-cells and also suggest that the administration of Reg protein and/or activation of the Reg gene can be used as a potential therapeutic approach for diabetes mellitus. We have further isolated several Reg and Reg-related genes from human, rat and mouse, and revealed that they constitute a multigene family, the Reg gene family. Based on the primary structures of proteins encoded by the Reg gene family, we have grouped the members of the family into three subclasses, type I, II, and III. Type I Reg (Reg I) encodes a beta-cell growth factor, Reg I protein, as mentioned above. Some of the type III Reg (Reg III) have recently been suggested to play roles in the regeneration of cells other than pancreatic beta-cells, such as neuronal cells and epithelial cells in the alimentary tract.

Amino Acid Sequence↗

PubMed2000

Frontiers of pancreas regeneration.

Recent advances in molecular biological techniques have made the search for the factors in pancreas regeneration more intensive. Many transcription factors and growth factors have been suggested to be involved in the proliferation, differentiation, and maintenance of endocrine and exocrine pancreas. Among the transcription factors, PDX-1 has been examined in a major pancreatectomy model and is suggested to play a role in beta-cell differentiation. Among the growth factors and related peptides, reg protein seems to be a promising candidate which can be applied to clinical practice. Our previous study showed that proton pump inhibitor-induced endogenous hypergastrinemia enhanced insulin secretion and pancreas regeneration. Our results and other studies have suggested that endogenous gastrin induces beta-cell differentiation. On the other hand, the role of classical gut hormones such as gastrin and cholecystokinin in pancreas regeneration has become less significant, as it has been shown that rodents deficient in the genes for these hormones form almost normal pancreas. Results in dogs have shown that pancreas regeneration occurs after major pancreatectomy. A preliminary experiment in primates also suggests latent developmental capacity in the adult primate pancreas. These results lead us to expect that regeneration of the remnant pancreas after subtotal pancreatectomy would be a good target of certain therapies to enhance pancreatic regeneration.

Adult↗

PubMed2005

Morphological study of rib regeneration following costectomy in adolescent idiopathic scoliosis.

This is a prospective observational study comparing cases with retrospective controls. The aim of the study is to compare rib regeneration with a scaffold placed intra-periosteally against no scaffold, after costectomy in adolescent idiopathic scoliosis. A prospective study was conducted at Amrita Institute of Medical Sciences on 16 consecutive patients (51 ribs) with adolescent idiopathic scoliosis who underwent costectomy and application of gel foam in the rib bed as a scaffold. These patients were compared with a retrospective group of 15 patients (33 ribs) who did not have the scaffold. All prospective and retrospective patients were followed up for a minimum period of 6 months and were analyzed radiographically for rib regeneration and morphology. A classification system was devised to include all possible morphologies of regenerate. The resulting data, when analyzed showed that majority of ribs re-grew to normal morphology in 3-6 months in the trial group. In comparison the regeneration in the retrospective controls was slower and poorer in quality. Ribs treated by placement of gel foam scaffold in the bed regenerate to a near normal radiological profile within 6 months of costectomy compared to a slower regeneration in those without gel foam scaffold.

Adolescent↗

PubMed2003

Effect of the rate of prestretching a peripheral nerve on regeneration potential after transection and repair.

We tested the influence of nerve stretch injury on nerve regeneration after cutting and suturing. An external fixator was used to lengthen the femur, and consequently the sciatic nerve, progressively, by 3 mm/day (5%/day: group I) or 5 mm/day (9%/day: group II). In both groups the total lengthening was 15 mm, corresponding to approximately 23%-28% elongation of the sciatic nerve. Seven days after initiating nerve lengthening, the external fixator was removed and the nerve was transected and sutured. At 2, 4, 6, or 8 weeks after this suturing, semithin sections were prepared from the sciatic and tibial nerves. Although regeneration of nerve fibers was observed beginning at 2 weeks in all groups, nerve regeneration showed a delay only in group II at 6 weeks, when group I showed nerve regeneration as good as in the unstretched control group. Differences in nerve regeneration after nerve lengthening at different rates were considered the result of mechanical nerve injury, nerve degeneration, ischemia, and fibrosis, all made worse with more rapid lengthening. Nerve lengthening at a more moderate rate (3 mm/day) did not appear to compromise regeneration.

Animals↗

PubMed2006

Regenerated soft tissue survival using repulsive force of magnetized devices: preliminary report.

BACKGROUND: Large full-thickness cartilage defects in the weight-bearing area are difficult to treat. A new therapeutic strategy called the total joint regeneration (TJR) system is proposed for such large defects. The purpose of this study was to evaluate the effects of the magnet-type TJR device using a rabbit model. METHODS: The magnetized devices were implanted in full-thickness chondral defects on the patellofemoral joints of rabbits. The specimens and surrounding tissue were harvested 4 weeks after the surgery and observed macroscopically and histologically. The thickness of the regenerated soft tissue on the femur joint surface was measured and compared. The difference between the two groups (magnetized and nonmagnetized) was significant at P < 0.05. RESULTS: Some cartilaginous regeneration was seen in the repair tissue. However, about half of the experimental knees were omitted from the study because of some trouble, such as loosening of the device or patella fracture. CONCLUSIONS: This study suggested that magnetized devices were useful for regenerating soft tissue by maintaining the joint space. Some hyaline cartilage-like tissue was regenerated partially on the magnetized devices. It was suggested that these devices might be useful for cartilage regeneration if the devices are improved.

Animals↗

PubMed2005

Active participation of apoptosis and mitosis in sublingual gland regeneration of the rat following release from duct ligation.

This study was designed to establish how mitotic cell proliferation and apoptotic cell death participate in the regeneration of atrophied rat sublingual glands. To induce atrophy to the sublingual gland of rats, the excretory duct was ligated unilaterally near the hilum, and after 1 week of ligation (day 0) the duct ligation was released to enable gland regeneration. The regenerating glands were examined with routine histology, immunohistochemistry for proliferating cell nuclear antigen (PCNA) as a marker of proliferating cells, terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) as a marker of apoptotic cells, and transmission electron microscopy. At day 0, a few acini and many ducts remained in the atrophic sublingual glands, and newly formed immature acini were observed at day 3. Thereafter acinar cells progressively matured and increased in number, although the number of ducts decreased. Many PCNA- and some TUNEL-positive cells were seen in acini and ducts during regeneration. The labeling indices for both cell types were statistically significantly different from that of the control at several time points of the regeneration. Apoptotic and mitotic cells were also confirmed to be present in the experimental sublingual glands by electron microscopy. These observations suggest that apoptosis as well as mitosis of duct and acinar cells actively participate in and play important roles in sublingual gland regeneration.

Animals↗

PubMed2005

TGF-beta1 favors the development of fast type identity during soleus muscle regeneration.

Transforming growth factor-beta1 (TGF-beta1) is known to be expressed in the environment of developing fast muscle fibres during ontogenesis. In the present study, we have examined effects of administration of either TGF-beta1 or neutralizing TGF-beta1 antibody on the induction of fast type phenotype in regenerating skeletal muscles in rats. Expressions of fast and slow myosin heavy chain (MHC) isoforms were studied using protein electrophoresis, at 3 and 6 weeks after myotoxic treatment. Muscle contractile properties were also measured in situ. The results have shown that a single injection of TGF-beta1 into the regenerating slow soleus muscle increased the expression of fast MHC-2x/d and MHC-2a and decreases that of slow MHC-1 (P<0.05). Moreover, it reduced the degree of tetanic fusion during contraction (P<0.05). Conversely, injection of neutralizing antibody against TGF-beta1 into the regenerating fast EDL muscle increased the expression of MHC-2a and MHC-1 (P<0.05). In conclusion, when the slow muscle was regenerating in the presence of an increased level of TGF-beta1, it induced a shift to a less slow MHC phenotype and contractile characteristics. Conversely, neutralization of TGF-beta1 in the regenerating fast muscle induced a shift to a less fast MHC expression. Together these results suggest that TGF-beta1 influences some aspects of fast muscle-type patterning during skeletal muscle regeneration.

Animals↗

PubMed2006

Acetylcholine receptors and nerve terminal distribution at the neuromuscular junction of long-term regenerated muscle fibers.

Mdx mice are deficient in dystrophin and show muscle fiber regeneration. Changes in the distribution of acetylcholine receptors have been reported at the neuromuscular junction of mdx mice and may be a consequence of muscle fiber regeneration. In this study, we examined whether the distribution of receptors was still altered in long-term, regenerated muscle fibers from C57Bl/10 mice. The left sternomastoid muscle of adult mice was injected with 60 microl of lidocaine hydrochloride to induce muscle degeneration-regeneration. In some mice, the sternomastoid muscle was denervated at the time of lidocaine injection. After 90 and 150 days, the nicotinic acetylcholine receptors were labeled with rhodamine-alpha-bungarotoxin for confocal microscopy. At both intervals studied, the receptors were distributed in spots. In denervated-regenerated fibers, the receptors were distributed as regular branches similar to denervated muscles without lidocaine treatment. These findings suggested that nerve-dependent mechanisms were involved in the changes in receptor distribution seen in regenerated muscle fibers after lidocaine treatment, and that a similar phenomenon could explain the changes in receptor distribution seen in dystrophic muscle fibers.

Animals↗

PubMed1982

A comparative study of plasma membrane Mg2+ -ATPase activities in normal, regenerating and malignant cells.

Plasma membranes have been prepared from rat normal liver cells, regenerating liver cells and Yoshida ascites hepatoma 66 cells after intact cells were first bound to polylysine-coated polyacrylamide beads, and the membrane-associated Mg2+ -ATPase activity was assayed directly on beads with membrane attached. With plasma membranes from normal liver cells, Km for ATP and V were found to be higher than those in regenerating liver cells and hepatoma cells. Vanadate caused a different sensitivity of the activity, without an effect in normal liver cells and with an inhibition in regenerating liver cells and hepatoma cells. The activity in normal and regenerating liver cells decreased with increasing temperature above 24-30 degrees C, while the activity in hepatoma cells continued to increase linearly to 37 degrees C. Unlike the enzyme in normal and regenerating liver cells, the hepatoma enzyme was shown to have a higher phase transition temperature and lower activation energies. In all three kinds of cells the activity was increased by the dephosphorylation of plasma membranes and unaffected by the phosphorylation. By means of histochemical Mg2+ -ATPase staining applied on polyacrylamide gels, at least three major bands which show the enzymic activity were visible in normal and regenerating liver and a single band was detected in hepatoma cells.

Adenosine Triphosphatases↗

PubMed1983

Intraocular tetrodotoxin in goldfish hinders optic nerve regeneration.

Repeated intraocular injection of tetrodotoxin (TTX) was used to produce a maintained block of neural activity in goldfish optic axons which were regenerating following a crush of the optic nerve. The recovery of visual function was delayed in the TTX-treated fish, as demonstrated by delays in the return of the startle reaction to sudden illumination, the dorsal light reflex and food pellet localization. A single injection of TTX at the time of optic nerve crush delayed recovery of the startle reaction but not of food localization. There was no loss of ganglion cells in the TTX-treated animals, but the number of regenerated axons detectable by light microscopy was reduced. Also, axonal transport of radioactively labeled protein in some of the regenerating axons showed a deficit at 21-28 days after the lesion, i.e., during innervation of the tectum. Incorporation of labeled amino acid into protein in the retinal ganglion cells was depressed during the same period, but both the transport and incorporation had returned to normal by 36 days after the lesion. These results, together with the results of the accompanying electrophysiological analysis of the effects of TTX58,59, suggest that TTX treatment interferes with two separate events in regeneration, one occurring soon after the nerve lesion and the other during innervation of the tectum. During at least the first of these events the effect of TTX treatment may be to reduce the number of size of the regenerating axon branches. We propose that the TTX effect may be mediated by a reduction in the axonal transport of certain materials, including gangliosides, nucleosides, or proteins specifically involved in regeneration.

Animals↗

PubMed1985

The response of optic tract glia during regeneration of the goldfish visual system. I. Biosynthetic activity within different glial populations after transection of retinal ganglion cell axons.

We monitored biosynthetic activity of optic tract glia during regeneration of retinal ganglion cell axons in the goldfish and found that the greatest level of incorporated [3H]thymidine and [3H]leucine occurred in glia by 10-15 days after axotomy. During this period there was a marked increase in the number of oligodendroglia and multipotential glia near the site of injury with no change occurring in the astroglial population. Electron microscopic autoradiography showed that oligodendroglia and multipotential cells incorporated 5-7-fold more thymidine than did cells of intact control preparations. Though all glial cell types incorporated more [3H]leucine during axonal regeneration, oligodendroglia and multipotential cells together accounted for more than 90% of measured radioactivity. In order to characterize glial-stimulating events specific to axonal regeneration, we produced axonal degeneration in the optic tract by removal of the retina. Optic tract glia during axonal degeneration incorporated less amino acid when compared to glia associated with regenerating axons. The degenerating optic tract also had less 2',3'-cyclic nucleotide 3'-phosphohydrolase, an enzyme produced by oligodendroglia, than that found in the regenerating visual system. Our results suggest that in response to ganglion cell axotomy oligodendroglia and multipotential glia of the goldfish optic tract proliferate. Moreover, regenerating axons provide one type of stimulant for glial protein biosynthesis.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗

PubMed1985

Long-term patterns of axon regeneration in the sciatic nerve and its tributaries.

The present study determines the numbers of axons that regenerate after sciatic nerve transection in the rat. The transections are done by removing either 4 mm or 8 mm of the nerve. The axons are counted in the gap and distal stump of the sciatic nerve and in 5 of its tributaries. Survival time is 9 months which we define as long-term to allow comparison with short-term data obtained after a much shorter survival. The first findings is that the numbers of axons in the gap and distal stump are different in the 2 transection paradigms. For the 4 mm paradigm, more axons than normal appear in the gap and only a fraction of these pass into the distal stump. For the 8 mm paradigm, the numbers of axons in the gap are normal and the numbers in the distal stump do not deviate far from these. Thus by changing only the length of the segment of removed nerve, one causes major differences in the numbers of axons that regenerate. Second the numbers of axons that regenerate in tributary nerves that innervate muscle have a different pattern than the numbers that regenerate into cutaneous nerves. Thus the factors control axonal numbers must be different in the 2 types of nerves. Finally, axons that regenerate into tributary nerves do not, by and large, regenerate in concert with those in the distal stump of the parent nerve. Thus the factors that control axonal numbers in the tributary nerves must be different from those that control the numbers in the distal stump of the parent nerve.

Animals↗