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PubMed1985

Alterations in fucosyl oligosaccharides of glycoproteins during rat liver regeneration.

[3H]Fucose-labelled glycopeptides in the slices of liver 24h after partial hepatectomy were fractionated on Sephadex G-50. Glycopeptides from regenerating liver contained a higher proportion of lower-Mr components than did controls. Regenerating liver contained a higher proportion of glycopeptides that were bound to concanavalin A-Sepharose and were subsequently eluted with 20mM-methyl alpha-D-glucopyranoside than did controls. Concanavalin A-bound glycopeptides from each source were entirely bound to a lentil lectin-Sepharose column. Both the concanavalin A-bound and -unbound fractions from regenerating liver were indistinguishable from the respective controls by Bio-Gel P6 column chromatography and neuraminidase digestion. These results show that fucosyl glycopeptides from regenerating liver contain a higher proportion of biantennary species with core fucose residues than do controls. Glycopeptides from regenerating livers 12h, 72h and 144h after partial hepatectomy were also examined; however, the difference was not significant. These observations suggest that the alterations in fucosyl glycopeptides may be related to rapid growth of hepatocytes 24h after partial hepatectomy. No significant difference was found in either [3H]mannose- or [3H]fucose-labelled glycoproteins from regenerating liver and from controls by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis, suggesting that the alteration in glycopeptides should depend on some differences in the late stage of oligosaccharide processing.

Animals↗
PubMed2002

lal-1: a differentially expressed novel gene during proliferation in liver regeneration and in hepatoma cells.

BACKGROUND: During liver regeneration, 95% of the resting hepatocytes enter in G1/S phase of the cell cycle. A number of hormones, growth factors and cytokines were identified that activate signal transduction pathways playing a primary role in hepatocyte proliferation. A wide and representative cDNA library containing 1.5 x 106 independent clones was constructed from regenerating liver in order to identify and characterize gene the products which play a crucial role in the first hours of the proliferative process of liver regeneration. RESULTS: A novel gene expressed in liver regeneration was cloned by subtractive hybridization. The putative protein displays in the N'-terminal a annexin-like domain and an aminopeptidase domain. We named the novel gene Liver Annexin Like-1 (lal-1). The lal-1 gene is modulated during liver regeneration, in hepatoma cells following physiological stimulation and after cAMP induction. CONCLUSION: The results indicate that lal-1 is involved in liver regeneration and that its expression is finely regulated during proliferative process. The isolation of lal-1 paves the way for a further characterization helping to assess lal-1 involvement in cell function and proliferation.

Animals↗
PubMed2002

Peripheral nerve regeneration in galactosaemic rats.

The use of galactosaemia as a model for some aspects of diabetic polyneuropathy allows the influence of glycation to be studied independently of other effects. There are well-studied abnormalities of the peripheral nerves in galactosaemic rats, one of which is that the efficiency of regeneration is initially reduced. One possible cause could be that glycated myelin debris in macrophages is less degradable and interferes with macrophage function. Macrophage recognition and ingestion of myelin glycosylated in vitro increases with the duration of incubation in a sugar-rich medium. This study was performed to investigate a possible correlation between galactosaemia and regeneration, together with the role of macrophages. Galactosaemia was induced by adding galactose to the rats' diet for 2 months before injury. Following a crush lesion to the sciatic nerve, regeneration was found to be delayed, demonstrated by a reduction in mean myelinated fibre size and density 1 month after crush, although, 2 and 3 months later, the differences did not reach statistical significance. There were also more macrophages in the galactosaemic rats than in the control animals at all time points. The initial delay in regeneration in galactosaemic rats was therefore only temporary and there was little evidence of long-term deleterious effects. In addition to the morphometric results, immunohistochemistry showed that there were more macrophages in the galactosaemic rats than in the control animals at all time points. Correlating macrophage and myelinated fibre counts suggests that the persistence of debris-containing macrophages does not appear to have a significant inhibitory effect on nerve regeneration. No evidence was found for persistent basal laminal tubes around the regenerating clusters.

Animals↗
PubMed1997

Expression of myosin heavy chain isoforms in regenerated muscle spindle fibres after muscle grafting in young and adult rats--plasticity of intrafusal satellite cells.

Satellite cells are the myogenic precursor cells of postnatal skeletal muscles. After muscle injury they can proliferate, differentiate, fuse and form myofibres. We have analysed regeneration of distinctly different types of intrafusal fibres in rat muscle spindles. We have introduced the new technique of heterochronous allotransplantation and compared it with the previously used standard autografting method. The allotransplantation method enables one to graft muscles from very young animals; we have used the extensor digitorum longus (EDL) muscles from 2- to 28-day-old rats, which were grafted into EDL muscles of adult inbred recipients. The regenerated "intrafusal" fibres did not express the spindle-specific slow tonic and alpha cardiac-like myosin heavy chain (MyHC) isoforms and they did not exhibit the dual mATPase reaction typical of the nuclear bag2 fibres and the characteristic regional differences in MyHC expression and in the mATPase reaction of nuclear bag1 and nuclear bag2 fibres. On the other hand, they expressed either fast twitch or slow twitch/beta cardiac MyHC isoforms and exhibited an alkali or acid stable mATPase reaction along their whole length, like extrafusal fast type 2 and slow type 1 muscle fibres, respectively. In all regenerated muscle spindles only motor, but no sensory axons were found. More than 85% of muscle spindles in our sample contained regenerated spindle fibres of the same extrafusal fibre type (either type 2 or type 1), in contrast to control muscle spindles, which always contained intrafusal fibres of three different intrafusal fibre types (nuclear bag1, nuclear bag2 and nuclear chain fibres). There were no differences in MyHC expression and mATPase activity between spindle fibres regenerated in grafts taken from young rats of various ages or between allotransplanted and autotransplanted EDL muscles. The present results demonstrate that regenerated "intrafusal" fibres resemble, according to MyHC expression, extrafusal fast or slow muscle fibres. It can thus be concluded that intrafusal satellite cells derived from distinctly different nuclear bag1, nuclear bag2 and nuclear chain fibres show great plasticity, as their MyHC expression can be respecified towards the extrafusal muscle fibre phenotype by foreign alpha-motor innervation.

Animals↗
PubMed2000

Molecular cloning and characterization of calreticulin, a calcium-binding protein involved in the regeneration of rice cultured suspension cells.

A full-length cDNA clone encoding a phosphoprotein (pp56) involved in the regeneration of rice (Oryza sativa L.)-cultured suspension cells was isolated by screening a rice cultured suspension cell cDNA library. The 1558-bp cDNA sequence contains an ORF encoding an acidic (pI 4.38) protein of 424 amino acids (47.9 kDa), sharing 70-93% and 50-53% homology with other plant and mammalian calreticulins, respectively. Sequence analysis of the cDNA clone revealed several significant conserved motifs, including a calreticulin family repeat motif in the central domain and two calreticulin family motifs in the N-domain, indicating that this gene is a rice calreticulin (CRO1). The CRO1 gene in long-term rice cultured suspension cells shows constitutive expression in both suspension culture and regeneration media. In contrast, expression of the CRO1 gene in short-term rice cultured suspension cells, which possess regeneration potential, is increased dramatically when these cells are transferred to the regeneration medium. After approximately 2 weeks in the regeneration medium, the expression of the CRO1 gene reverts to constitutive levels. These results demonstrate the presence of calreticulin in rice cultured suspension cells and its developmental regulation during the regeneration of rice cultured suspension cells.

Amino Acid Sequence↗
PubMed2002

Dissecting planarian central nervous system regeneration by the expression of neural-specific genes.

The planarian central nervous system (CNS) can be used as a model for studying neural regeneration in higher organisms. Despite its simple structure, recent studies have shown that the planarian CNS can be divided into several molecular and functional domains defined by the expression of different neural genes. Remarkably, a whole animal, including the molecularly complex CNS, can regenerate from a small piece of the planarian body. In this study, a collection of neural markers has been used to characterize at the molecular level how the planarian CNS is rebuilt. Planarian CNS is composed of an anterior brain and a pair of ventral nerve cords that are distinct and overlapping structures in the head region. During regeneration, 12 neural markers have been classified as early, mid-regeneration and late expression genes depending on when they are upregulated in the regenerative blastema. Interestingly, the results from this study show that the comparison of the expression patterns of different neural genes supports the view that at day one of regeneration, the new brain appears within the blastema, whereas the pre-existing ventral nerve cords remain in the old tissues. Three stages in planarian CNS regeneration are suggested.

Amino Acid Sequence↗
PubMed1999

Does steatohepatitis impair liver regeneration? A study in a dietary model of non-alcoholic steatohepatitis in rats.

BACKGROUND: Impaired liver regeneration is a feature of alcoholic hepatitis, but the relative importance of alcohol, nutritional imbalance and inflammatory mediators in causing this effect is unclear. Non-alcoholic steatohepatitis (NASH) is a form of liver disease with similar morphology to alcoholic hepatitis, but the effect of this disorder on liver regeneration is unclear. We, therefore, examined the status of liver regeneration in a rat nutritional model of hepatic steatosis with inflammation, which is morphologically identical to NASH in humans. METHODS: Male Wistar rats received a methionine-choline-deficient diet (MCDD) for 4 weeks before experiments and both isocaloric pair-fed and ad libitum-fed rats were used as controls. Following partial hepatectomy (68%), the extent of hepatic regeneration was determined 24 h later using [3H]-thymidine incorporation and restitution of liver mass. RESULTS: There was no significant difference of [3H]-thymidine incorporation in MCDD-fed, pair-fed and ad libitum-fed rats (80+/-27, 78+/-11 and 80+/-6.3 d.p.m./microg DNA, respectively). Similarly, restituted liver masses in three groups of rats were not significantly different (17+/-3.8, 18+/-1.8 and 17+/-3.1% initial liver weight, respectively). CONCLUSIONS: The similarities in hepatic histology and cytochrome P450 2E1 induction between this nutritional model of hepatic steatohepatitis and alcoholic steatohepatitis imply that these two disorders share pathogenetic mechanisms. However, liver regeneration is not altered by NASH in rats, indicating that the nutritional and inflammatory changes that appear similar to those of alcoholic liver disease do not cause impairment of liver regeneration.

Animal Feed↗
PubMed1999

Protection of regenerating liver after partial hepatectomy from carbon tetrachloride hepatotoxicity in rats: role of hepatic stimulator substance.

BACKGROUND: In the present study, we examined the effect of hepatic stimulator substance (HSS) on modulating hepatotoxicity induced by carbon tetrachloride (CCl4) in the regenerating rat liver. METHODS: Hepatotoxicity was induced in vivo by administering CCl4 to rats that had undergone a 68% partial hepatectomy (PH). In vitro studies were also performed in hepatocytes isolated from PH rats. RESULTS: Hepatic stimulator substance was extracted from regenerating rat liver 96 h after PH and its activity, as determined according to the method of LaBrecque, reached its maximum 96 h after PH. At this time, the mortality induced by CCl4 was significantly decreased in PH rats compared with sham-operated rats (18 vs 59%, P < 0.01). Likewise, changes in serum alanine aminotransferase (ALT) or bilirubin induced by CCl4 were less in rats after 96 h PH. The resistance of regenerating hepatocytes to CCl4 was retained in in vitro samples. Thus, leakage of intracellular ALT or aspartate aminotransferase induced by CCl4 in hepatocytes from 96 h hepatectomised rats was less than in control hepatocytes. HSS demonstrated a protective effect on hepatocytes against CCl4 both in vivo and in vitro. In additional studies, regenerating liver showed increased mitochondrial respiratory activity and enhanced plasma membrane fluidity. The HSS was also shown to increase hepatic mitochondrial respiratory activity and enhance plasma membrane fluidity. Further, the protective effect induced by HSS was correlated with the restoration of mitochondrial respiratory activity and plasma membrane fluidity induced by CCl4. CONCLUSIONS: Regenerating rat liver exhibits resistance to CCl4-induced hepatotoxicity, and the protection afforded by the regenerating state can be attributed, at least in part, to HSS-induced increases in mitochondrial respiratory activity and plasma membrane fluidity.

Alanine Transaminase↗
PubMed1995

Nerve growth factor promotes neurite regeneration in PC12 cells by translational control.

When PC12 cells are primed with nerve growth factor (NGF) for periods of > or = 1 week, they acquire the ability to regenerate neurites rapidly in response to NGF. It is not known how NGF promotes this regeneration, but it does not require ongoing RNA synthesis. Previous studies have suggested that NGF directs the accumulation of precursor molecules that are rapidly assembled to form the regenerated neurites. To address the nature of these precursor molecules, we have treated PC12 cells with macromolecular synthesis inhibitors during the priming and regeneration phases of neurite growth. Here we show that NGF promotes neurite regeneration by inducing the synthesis of new proteins. These proteins are encoded by short-lived mRNAs that are generated during the NGF priming period. The isolation and identification of these mRNAs will allow a further understanding of how NGF promotes neurite regeneration.

Animals↗
PubMed1995

Okadaic acid and cultured frog sciatic nerves: potent inhibition of axonal regeneration in spite of unaffected Schwann cell proliferation and ganglionic protein synthesis.

Okadaic acid (OA) is a frequently used phosphatase inhibitor that by inhibiting dephosphorylation increases the net phosphorylation level in various systems. In the present study OA was used to assess the role of balanced phosphorylation-dephosphorylation reactions for successful regeneration of peripheral nerves. To achieve this, the effects of OA on phosphorylation levels, neurite outgrowth, injury-induced support cell proliferation, and neurofilament stability, respectively, were investigated in the in vitro regenerating, adult frog sciatic sensory nerve. OA at a moderate concentration (20 nM) increased phosphorylation levels and almost completely inhibited the in vitro regeneration in a reversible way. The effect on regeneration was not due to induced neurofilament instability and was only seen when the drug was applied in the outgrowth region. The latter and the absence of effects on support cell proliferation indicate that OA acts locally at the level of newly formed axons. However, the inhibition of regeneration was not a consequence of reduced delivery of proteins by axonal transport, because this process in fact was increased by OA. Altogether, the study suggests that properly balanced phosphorylating-dephosphorylating reactions are critical for regeneration of peripheral nerves.

Animals↗
PubMed2000

Combined interleukin 6 and soluble interleukin 6 receptor accelerates murine liver regeneration.

BACKGROUND & AIMS: Liver regeneration after loss of hepatic tissue leads to hepatocyte and nonparenchymal cell proliferation and rapid restoration of liver parenchyma. Interleukin (IL)-6 is a key inducer of transcription factors involved in liver regeneration. Whenever IL-6 activates target cells, it binds to a specific IL-6 receptor (IL-6R). The IL-6/IL-6R complex then associates with the signal transducer gp130, leading to activation of intracellular signaling. METHODS: We have recently constructed the designer cytokine Hyper-IL-6 consisting of soluble IL-6R covalently linked to IL-6, which directly stimulates gp130 even in the absence of membrane-bound IL-6R. We compared the influence of IL-6 and Hyper-IL-6 on liver regeneration after partial hepatectomy in mice. RESULTS: The IL-6/soluble IL-6 fusion protein Hyper-IL-6, but not IL-6 alone, led to an earlier onset of hepatocellular proliferation resulting in an acceleration of liver weight restoration. Also, during liver regeneration, soluble IL-6R levels were increased. CONCLUSIONS: These results emphasize a central role for IL-6 and soluble IL-6R in liver regeneration and indicate a possible therapeutic potential for the designer cytokine Hyper-IL-6 in clinical situations associated with liver regeneration such as acute hepatic failure or resection of chronically damaged liver tissue.

Animals↗
PubMed2005

Amphiregulin: an early trigger of liver regeneration in mice.

BACKGROUND AND AIMS: Liver regeneration is a unique response directed to restore liver mass after resection or injury. The survival and proliferative signals triggered during this process are conveyed by a complex network of cytokines and growth factors acting in an orderly manner. Activation of the epidermal growth factor receptor is thought to play an important role in liver regeneration. Amphiregulin is a member of the epidermal growth factor family whose expression is not detectable in healthy liver. We have investigated the expression of amphiregulin in liver injury and its role during liver regeneration after partial hepatectomy. METHODS: Amphiregulin gene expression was examined in healthy and cirrhotic human and rat liver, in rodent liver regeneration after partial hepatectomy, and in primary hepatocytes. The proliferative effects and intracellular signaling of amphiregulin were studied in isolated hepatocytes. The in vivo role of amphiregulin in liver regeneration after partial hepatectomy was analyzed in amphiregulin-null mice. RESULTS: Amphiregulin gene expression is detected in chronically injured human and rat liver and is rapidly induced after partial hepatectomy in rodents. Amphiregulin expression is induced in isolated hepatocytes by interleukin 1beta and prostaglandin E(2), but not by hepatocyte growth factor, interleukin 6, or tumor necrosis factor alpha. We show that amphiregulin behaves as a primary mitogen for isolated hepatocytes, acting through the epidermal growth factor receptor. Finally, amphiregulin-null mice display impaired proliferative responses after partial liver resection. CONCLUSIONS: Our findings indicate that amphiregulin is an early-response growth factor that may contribute to the initial phases of liver regeneration.

Adult↗
PubMed1996

Influence of continuous interleukin-2 administration via the portal vein on liver regeneration following partial hepatectomy in rats.

We have reported the efficacy of intraarterial-combined immunochemotherapy including interleukin-2 (IL-2) for unresectable hepatocellular carcinoma (HCC). To further test this therapy for prevention of intrahepatic recurrence after hepatectomy, the influence of IL-2 on liver regeneration was examined using mitotic index (MI) and the bromodeoxyuridine (BrdU) labeling index (LI) in 70% hepatectomized Donryu rats. In addition, gap junction appearance, which may change during liver regeneration, was analyzed using a monoclonal antibody (HAM8). Serum albumin, alanine transaminase, and total bilirubin (TB) levels were also evaluated. IL-2 (45,000 Japanese reference units [JRU]/d) or saline was administered continuously via the portal vein immediately after hepatectomy using an infusion pump. We also examined the influence of IL-2 on liver regeneration after hepatectomy with splenectomy. No difference in the weight of the liver, serum albumin, alanine transaminase, or TB was observed in any groups at 1, 2, or 4 days after hepatectomy. Neither IL-2 nor splenectomy influenced MI and BrdU LI at all three points. Gap junctions began to disappear after hepatectomy and reached a minimum on day 2 in all groups. Four days after hepatectomy, the density of the reappearing gap junctions was markedly lower in groups treated with IL-2 than in those receiving saline with or without splenectomy. However, the density returned to close to preoperative levels 6 days after hepatectomy in all groups. Continuous portal infusion of IL-2 transiently disturbed gap junction reappearance during liver regeneration. However, no other parameters of liver regeneration or liver functions differed. These results suggest that the liver regeneration after partial hepatectomy may be suppressed by the administration of IL-2, even though the suppression may not be harmful for overall recovery of the resected liver. However, it seems that hepatic IL-2 administration can be performed without serious complications after hepatectomy.

Alanine Transaminase↗
PubMed2001

Axonal regeneration stimulated by the combination of nerve growth factor and ciliary neurotrophic factor in an end-to-side model.

The aim of this study was to investigate the potential for stimulating axonal regeneration in the context of end-to-side coaptation using a combination of nerve growth factor and ciliary neurotrophic factor in the rat sciatic nerve model. Four experimental groups (n = 8) were used: end-to-side coaptation only, end-to-side coaptation plus growth factor injection, primary repair, and nontransferred gap control. Twenty weeks after surgery histologic analysis showed that the ratio of axon density was significantly increased for the growth factor injection group. Histologic evidence suggested contamination from the proximal peroneal stump. Electrical stimulation and muscle weights showed that the target muscles had been reinnervated in all groups except the nontransferred gap control group. These data support the conclusion that the use of nerve growth factor and ciliary neurotrophic factor in combination may enhance regeneration in the peripheral nervous system. This is consistent with previous reports on the central nervous system and suggests a potential application in future studies aimed at improving peripheral nerve regeneration. Another conclusion is that contamination from the proximal peroneal stump may explain the regeneration observed in the end-to-side model. Further study using retrograde labeling is needed to establish the origin of the regenerating axons. Finally, evidence suggests that regenerating axons can use the epineurium of an intact nerve to bridge a gap in continuity.

Anastomosis, Surgical↗
PubMed2001

Mineralization dynamics of regenerate bone during mandibular osteodistraction.

Distraction osteogenesis offers an alternative approach for the correction of craniofacial deformities, yet little substantive data is available regarding mineralization of the forming regenerate. The purpose of this study was to evaluate, by plain film radiography and digital subtraction radiography, the mineralization dynamics of regenerate bone during osteodistraction. Thirteen skeletally mature male beagle dogs underwent 10 mm of bilateral mandibular distraction osteogenesis, at which time the bone was allowed to consolidate for either 4, 6, or 8 weeks. The tissues were then evaluated clinically and radiographically. The results demonstrate that several different types of regenerate are evident during mineralization of the distraction gap. A classification system is presented based on the length, width, and density of the mineralizing regenerate, as well as the presence or absence of an interzone. It appears that important factors for determining regenerate stability are the presence or absence of an interzone, as well as the width of the regenerate relative to the host bone segments. Finally, in cases where an interzone is present, subtraction radiography may provide a means of evaluating the level of mineralization within the interzone as well as the dynamics of mineralization over the course of distraction and consolidation.

Animals↗
PubMed2002

Peripheral nerve regeneration in the apolipoprotein-E-deficient mouse.

Apolipoprotein E (apo E) is thought to mediate the reutilization of myelin cholesterol for nerve regeneration. Prior research suggests that apo E is not essential for nerve regeneration following a nerve crush injury. This study was conducted to determine if apo E is essential for nerve regeneration after nerve transection and interposition nerve autograft. Nerve regeneration of transgenic apo E-deficient mice was compared with control mice after a sciatic nerve neurolysis and repair and interposition autograft. Histomorphometric assessment and histology were performed on distal nerve segments to evaluate nerve regeneration. Apo E-deficient mice demonstrated no difference in total fiber number or nerve fiber width when compared with controls; however, the nerve fiber density and percent neural tissue of apo E-deficient mice were significantly less than controls following nerve repair. Apo E deficiency does not affect nerve regeneration. It is likely that the low nerve fiber density and the low percent neural tissue associated with apo E-deficiency result from impairment in the disposal of myelin debris.

Animals↗
PubMed1999

Strain differences in peripheral-nerve regeneration in rats.

Currently, several strains of rats are used for studies of peripheral-nerve injury and repair. The purpose of this study was to determine if significant differences in regeneration between strains exist that might influence comparison of results and interpretation of scientific conclusions. One outbred (Sprague-Dawley) and four inbred stains (ACI, Wistar-Furth, Lewis, Brown-Norway) were studied. Animals were randomized to one of two experimental conditions, undergoing either posterior tibial nerve transection and repair, or Silastic conduit repair of the posterior tibial nerve (n=6/group). Endpoint evaluations at 6 and 13 weeks included histomorphometry and walking-track analysis. Evidence of excellent regeneration was noted in all rat strains undergoing primary repair. Generally, no statistically significant differences between strains were noted, regardless of endpoint evaluation used in the primary repair group. Nerve regeneration across the conduits was either poor or not present at 6 weeks, with no regeneration at all noted in any animals in the ACI and Brown-Norway groups, and regeneration in only one or two animals in the other strains. At 13 weeks, between three and five animals in each strain showed regeneration, but functional recovery was poor. Overall, few differences in peripheral-nerve recovery appear to exist between rat strains. It seems that uniform conclusions may be drawn regardless of strain used.

Analysis of Variance↗
PubMed1996

The selectivity of regenerating motor and sensory axons.

Functional results of peripheral nerve repair have been hampered by misdirection of regenerating axons. The purpose of this study was to determine in a rat femoral nerve model whether regenerating motor and sensory axons from a proximal nerve stump select the appropriate distal motor or sensory branch. In two experiments, the proximal stump of the motor or sensory branches was sutured to the distal motor sensory stumps, so that the three branches were parallel and the three transected ends faced in the same direction. More regenerated axons from both the proximal motor and sensory stumps entered the distal sensory stump. The number of misdirected axons did not decrease over time. The selective regeneration of motor axons toward the distal motor stump could not be validated. In this study, neurotropism appeared to play a measurable role in sensory axon regeneration, but not in motor axon regeneration. Pruning of the misdirected axons was not demonstrated.

Animals↗