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PubMed1996

Liver regeneration 3: Regulation of signal transduction during liver regeneration.

The liver has a tremendous capacity to regenerate. For example, after extensive hepatic resection, remaining hepatocytes proliferate to restore the mass of the organ within days to weeks. This proliferative response is fascinating because hepatocytes rarely replicate in the healthy adult liver. Instead, these cells perform highly specialized functions and exemplify mature, terminally differentiated cells. Therefore it is somewhat surprising that the liver can repopulate while performing its many obligate, organ-specific functions. Study of the regenerating liver remnant after partial hepatectomy has helped to delineate mechanisms that regulate proliferation and liver-specific functions in individual hepatocytes, as well as those that coordinate the behaviors of different liver cell populations to balance organ growth and tissue-specific gene expression. Hence, this review will focus on inter- and intracellular signals that regulate the hepatocyte phenotype after PH.

Animals↗
PubMed1996

Liver regeneration 7. Prometheus' myth revisited: transgenic mice as a powerful tool to study liver regeneration.

In this review, we present examples of the contribution of transgenic mice to our knowledge concerning the type of cells that are able to repopulate a damaged liver and information on the factors and mechanisms involved in postnatal liver growth and regeneration. The transgenic technology offers the opportunity to evaluate the physiological consequences of perturbating expression of a given gene in vivo. It has provided insights into the concerted action of extracellular (HGF/SF, TGF-alpha, EGF, TGF-beta) and intracellular factors (c-myc, c-fos, c-jun, p53, c-met, and others) in liver regeneration. Transgenic mice can also contribute to the dissection of the molecular mechanisms responsible for the regulated expression of these factors, both at the transcriptional and the posttranscriptional level. An illustration of such a strategy is given by the study of the sequences involved in the posttranscriptional regulation of the c-myc proto-oncogene. The recent improvement of gene targeting, in which endogenous genes are inactivated by homologous recombination, represents a further step toward the study of the function of a particular gene. Inactivation of most of the factors described in this review has been undertaken. However, further studies of their role in liver growth control are impeded by the fact that the corresponding knockout mice die prematurely. This problem could be overcome by the advent of new techniques, which will be briefly presented, aimed at turning genes on and off at will and in a tissue-specific manner.

Animals↗
PubMed1998

Sensory neurons regenerate more dominantly than motoneurons during the initial stage of the regenerating process after peripheral axotomy.

This study was designed to determine whether sensory neurons or motoneurons were dominant during the earlier stage of the regeneration process after peripheral axotomy. After transection of the right sciatic nerves of rats, epineurial end neurorrhaphy was performed. At 5, 7 and 14 days postoperatively, the nerves were re-transected at the positive pinch site, and their proximal stumps were exposed to the retrograde neurotracer, Fluoro-Gold (F-G). Seventy-two hours later, the lumbar spinal cords and the L4 and L5 dorsal root ganglia (DRG) were harvested and evaluated. The incidence and the intensity of F-G labelling in DRG were significantly higher than in anterior horns (AH). These results demonstrated that sensory neurons were more dominant than motoneurons in nerve regeneration.

Animals↗
PubMed2004

Alleviated tension at the repair site enhances functional regeneration: the effect of full range of motion mobilization on the regeneration of peripheral nerves--histologic, electrophysiologic, and functional results in a rat model.

BACKGROUND: In the clinical management of combined tendon and nerve injuries, competing treatment strategies are well known. The effect of mobilization on the functional regeneration of peripheral nerves remains controversial. This study sought to determine the effect of full range of motion mobilization on nerve repair by using tubular segmental nerve splinting to block movement, and thereby variable tension, at the nerve repair site. METHODS: In 96 rats, the right sciatic nerve was transected midthigh and coapted immediately microsurgically. The groups used in the study were as follows: group N, epineural nerve repair; group T, segmental tubular nerve splinting with fixed in situ tension at the nerve suture site,allowing segmental movement only; group TN, segmental tubular nerve splinting with alleviated in situ tension at the nerve suture site, allowing segmental movement only; and group TM, segmental tubular nerve splinting without fixed in situ tension at the nerve suture site, allowing movement of the nerve suture site. Full range of motion of the lower limbs was ensured by passive motion of hind limbs once a week after functional testing. Blinded histologic, immunohistochemical, and electrophysiologic assessment and 12 postoperative weekly function tests were carried out. RESULTS: Functional and electrophysiologic results were significantly better in group TN, by segmental tubular nerve splinting with alleviated in situ tension at the nerve repair site, mainly because of less scar formation and enhanced endoneural angiogenesis at the nerve suture segment. CONCLUSION: Full range of motion mobilization may impede functional nerve recovery by significant endoneural collagenization and decreased angiogenesis at the nerve suture segment. Complete alleviation of in situ (pathophysiologic) tension at the nerve suture site seems to improve functional peripheral nerve regeneration.

Animals↗
PubMed2007

Electrically conductive biodegradable polymer composite for nerve regeneration: electricity-stimulated neurite outgrowth and axon regeneration.

Normal and electrically stimulated PC12 cell cultures and the implantation of nerve guidance channels were performed to evaluate newly developed electrically conductive biodegradable polymer composites. Polypyrrole (PPy) doped by butane sulfonic acid showed a significantly higher number of viable cells compared with PPy doped by polystyrenesulfonate after a 6-day culture. The PC12 cells were left to proliferate for 6 days, and the PPy-coated membranes, showing less initial cell adherence, recorded the same proliferation rate as did the noncoated membranes. Direct current electricity at various intensities was applied to the PC12 cell-cultured conductive membranes. After 7 days, the greatest number of neurites appeared on the membranes with a current intensity approximating 1.7-8.4 microA/cm. Nerve guidance channels made of conductive biodegradable composite were implanted into rats to replace 8 mm of sciatic nerve. The implants were harvested after 2 months and analyzed with immunohistochemistry and transmission electron microscopy. The regenerated nerve tissue displayed myelinated axons and Schwann cells that were similar to those in the native nerve. Electrical stimulation applied through the electrically conductive biodegradable polymers therefore enhanced neurite outgrowth in a current-dependent fashion. The conductive polymers also supported sciatic nerve regeneration in rats.

Absorbable Implants↗
PubMed1989

Genetic analysis of developmental mechanisms in hydra. XIX. Stimulation of regeneration by injury in the regeneration-deficient mutant strain, reg-16.

A mutant strain of Hydra magnipapillata, reg-16, has a very low regenerative capacity. After head removal, it usually restores 10-20% of the original number of tentacles in 7 days. A procedure was found to markedly improve tentacle regeneration in this strain. The closed wound located at the apical regenerating tip of the decapitated polyp was gently reopened using a pair of forceps. Reg-16 polyps treated in this way at 24 and 48 h after head removal restored nearly all of the original number of tentacles in 7 days. A lateral tissue transplantation procedure was employed to examine the effect of wound reopening on the morphogenetic potential of decapitated reg-16 polyps. Wound reopening produced a significant increase in head activation level without producing a preceding decrease in head inhibition level. This and other observations suggest that the coupled activation-inhibition changes that normally occur after head removal from the wild-type hydra do not occur in this strain. Mechanisms responsible for the wound reopening effect and the absence of activation-inhibition coupling in the mutant strain reg-16 are discussed.

Animals↗
PubMed1996

The exogenous administration of basic fibroblast growth factor to regenerating skeletal muscle in mice does not enhance the process of regeneration.

The effects, in vivo, of the exogenous administration of bFGF on myogenesis of regenerating skeletal muscle was assessed either morphometrically or autoradiographically in three separate models of muscle injury in mice: crush-injured, denervated, and dystrophic (mdx) muscles. The bFGF was administered at various doses and different time schedules, sometimes in combination with heparin, into injured tibialis anterior muscles of mice. Delivery of the bFGF was either by direct intramuscular injection or by the sustained release from 888polymers (Hydron or Elvax) implanted into the muscles. The bioactivity of bFGF was confirmed in vitro by measuring its ability to stimulate the proliferation of BALB/c-3T3 fibroblasts and muscle precursor cell lines. The ability of bFGF to stimulate angiogenesis in vivo was confirmed by the implantation of controlled-release polymers containing bFGF into the normally avascular cornea of rats. No measurable effect of bFGF was seen in any of the models of skeletal muscle injury under these experimental conditions, indicating that the availability of biologically active bFGF is not a limiting factor in the regeneration of skeletal muscle following injury.

Animals↗
PubMed1976

[Quantitative studies on the regeneration of myelinated nerve fibers. II. Variations of the number and size of regenerating nerve fibers after localized crushing or total section].

1. The number and size of myelinated nerve fibers have been determined at standard levels, in the nerve to medial head of right and left gastrocnemius muscles of 112 rats in which the left sciatic nerve had suffered an experimental lesion according one of the following four modalities: localized crushing, total section followed or not by suture and resection of a nervous segment of about 1 cm. 2. In the nerve to medial head of right gastrocnemius muscle (contralateral nerve used as control), the number of myelinated fibers decreased in average to 10% after crushing, 5% or 4% after section followed or not by suture. However, an increase of 6% was observed after resection. The mean values of the mean diameters showed a decrease of 8% after crushing and 5% after section without suture. This value did not seem to be affected by section followed by immediate suture and after resection, it increased of 11%. On the whole, male rats appeared to be more sensitive than female to the effects of the operation. 3. The nerves of 12 rats have been observed from 15 to 334 days after resection of about 1 cm of sciatic nerve. The 20% of the regenerating myelinated nerve fibers which have succeeded to cross over such a distance had a distribution which remained unimodal; the diameter of the large fibres did not exceed 8 micronm. 4. 34 rats have been sacrificed from 15 to 715 days after sciatic nerve section which was not followed by suture. The number of myelinated nerve fibers became normal again during the 4th month and reached afterwards a mean value of 130%, with very marked variations. The nerve fibre distribution was most frequently unimodal, but may came bimodal one year after the operation in certain nerves. Their mean diameter never exceeded 60% of the normal. 5. The nerves of 34 rats have been examined from 15 to 720 days after section and immediate suture. The number of myelinated nerve fibers returned to normal during the second month and increased afterwards to an average of 150% with very important variations. The nerve fiber distribution was generally unimodal, but may become bimodal 7 months after the operation. Their mean diameter reached only 50 to 55% of the normal. 6. 32 rats have been sacrificed from 10 to 720 rats after a localized crushing. The number of myelinated nerve fibers come back to normal during the 4th week and later increased up to a mean of 115%. Their distribution became early bimodal from the 97th day onwards. Although, their mean diameter nerver exceeded 80% of the normal, the histograms of the regenerating nerve and of the control nerve could be almost superposed during the second year.

Animals↗
PubMed2006

[Spinal cord regeneration in rats after thoracic segmentectomy: growth and regeneration of nerve fibers].

As it was described in a previous paper (Morphology, 2005, v.127, Iss. 2), spinal cord (SC) consolidation after thoracic segmentectomy in rats took place via connective tissue scar formation in the area of trauma, which was accelerated when SC defect was filled with by the collagen gel (Spherogel). In this paper, on the basis of semithin section analysis and transmission electron microscopic study, it was shown that regenerating nerve fibers crossed the connective tissue within the formations, which were structurally identical to peripheral nerves. In the zones of rarified SC substance, caudally to the site of trauma, myelination of growing axons was realized by glial cells without the formation of the nerve truncs. In the white matter, within the fasciculi of SC lumbar segments, multiple thin regenerating fibers were seen in the area of degenerated myelinated nerve fibers.

Animals↗
PubMedDate not supplied

Intestinal epithelium regeneration in rats receiving methotrexate and a trial of regulating this regeneration with pentagastrin and glucagon.

The study was carried out in three groups of rats: group I of 36 rats received methotrexate, group II of 36 rats were given methotrexate, pentagastrin and glucagon, group III of 12 rats served as control. For histological examination the ileum was taken from the animals killed on days 1, 2, 3, 4, 7 and 9 after the last injection of methotrexate. Besides histological examinations the mitotic index and the number of cells in crypt longitudinal-section were determined. Relatively low doses of methotrexate caused characteristic changes in the intestinal mucosa: disappearance of mitotic figures, shortening of crypts particularly on the first day after the last dose of methotrexate. On the following days regeneration processes were noted causing an excessive epithelial proliferation observed up to the 9th day after the last dose of methotrexate. This indicates that the mobilized mechanisms of epithelial proliferation stimulation exert their effect fairly long. In the group receiving methotrexate administration of pentagastrin and glucagon contributed to the increased number of mitoses in crypt epithelium and the number of cells on crypt longitudinal-section. These observations are an evidence of a beneficial effect of the hormones administered to the rats in the regeneration of the ileal epithelium damaged by the cytostatic agent.

Animals↗
PubMed1986

[Liver regeneration and the immune system. III. Suppressor activity of splenic adherent cells activated in vivo by liver regeneration].

It has been shown in the previous reports the immune system of mice is activated during liver regeneration following partial hepatectomy and lymph node cells activated in vivo suppress the syngeneic mixed hepatectomized liver cell-lymphocyte reaction (sMLHLR). In this report, it is demonstrated that the suppressor activity of lymphocytes in vivo by liver regeneration exists in lymph node T cells and splenic adherent cells, but not in lymph node B cells. This suppressive activity of splenic adherent cells is blocked with indomethacin or aspirin. Each of these compounds in nontoxic doses inhibited macrophage-mediated suppression suggesting that the release of prostaglandins by macrophages played an essential role in inhibiting the sMLHLR.

Animals↗
PubMed1977

[Eyestalk removal and intensive regeneration: joint effects on the molting cycle of Pachygrapsus marmoratus (Crustacea, Decapoda), variability of the critical regeneration stage].

When eyestalk-removal and pereiopod-removal, followed by intensive regeneration, are realized together on the same animal, their accelerative effect on the moulting rate is lower than the effect of only one of these two processes. The critical stage of pereiopod regeneration varies between the moulting stages C4 to D1 according to the physiological state of the Crab.

Animals↗
PubMed1980

On the role of germ cells in planarian regeneration. II. Cytophotometric analysis of the nuclear Feulgen-DNA content in cells of regenerated somatic tissues.

Previous findings by our group have shown how primordial male germ cells take part in regenerative blastema formation in planarians by migrating to the wound. The role of these cells in rebuilding transected tissues has been investigated in a population of Dugesia lugubris s.l. which is particularly suited for our purpose. In fact, these planarians provide a clear karyological marker to distinguish diploid male germ cells (2n = 8) from tryploid embryonic or somatic cells (3n = 12). In this study we employed the cytophotometric analysis of the nuclear Feulgen-DNA content in order to distinguish non-replicating male germ cells from reserve and somatic cells. The Feulgen-DNA content in cells from the gonad-free caudal area was measured after complete regeneration. Most non-replicating cells (94-95%) were found to have a DNA amount typical of cells previously estimated as triploid. Some (5-6%) nuclei containing a DNA amount typical of cells previously estimated as diploid male gonia were also found. These findings seem to support the view that primordial male germ cells also participate in rebuilding somatic tissues according to the field influence they encounter during regeneration. The possibility that metaplasia (or cell transdifferentiation) may occur in planarians is finally discussed.

Animals↗
PubMed1996

Hepatic regeneration. The role of regeneration in pathogenesis of chronic liver diseases.

Hepatic necrosis is a common reaction to liver injury of various etiologies. The response is regeneration. As reviewed earlier, reconstitution of liver mass may proceed via two mechanisms: (1) re-entry of surviving, functionally intact differentiated liver cells into the cell cycle, where they may remain for several rounds of replication, and (2) recruitment of hepatic progenitor cells, whereby the liver mass is replaced by extensive proliferation and differentiation of more primitive cell types. Although both mechanisms appear to share a number of regulatory factors, distinct differences exist that are reflected in the complex and intricate networks of interacting cells, cytokines, and ECM molecules constituting the regenerative process. The development of liver fibrosis or cirrhosis is probably an unwanted but frequent byproduct of the regenerative process, similar to scar formation in any other tissue following extensive damage. Although intensive research in recent years has yielded a wealth of information about regenerative processes, a better understanding of the elements regulating the regenerative process is crucial for effective intervention to prevent or minimize fibrosis while providing optimal conditions for regeneration. Because our only experimental tool is observation in human studies, we must continue the use of experimental animal models including those of transgenic mice to further elucidate the complex interactions of cytokines, ECM, and target cells in the development of liver fibrogenesis, cirrhosis, and cancer.

Animals↗
PubMed1997

[Increase in the level of augmenter of liver regeneration mRNA in the rat regenerating liver after partial hepatectomy].

Augmenter of liver regeneration (ALR) is a novel hepatic stimulator. After 70% of the rat liver was removed, ALR-like activity in the remnant liver began to increase within 24 h. In parallel with the activity, the ALR mRNA level in the remnant liver increased 12 h after the operation and reached a maximum in 24 h. These findings indicate that the liver itself produces ALR, which may be a hepatotropic factor acting as a trigger for liver regeneration.

Animals↗
PubMed1997

Periodontal regeneration in naturally occurring Class II furcation defects in beagle dogs after guided tissue regeneration with bioabsorbable barriers.

THE EFFICACY OF A BIOABSORBABLE polylactic acid based barrier was evaluated using naturally occurring buccal Class II furcation defects in beagle dogs. Sixteen furcation sites (8 control and 8 experimental) were treated in 6 adult animals. After full thickness flap reflection, exposed furcations and root surfaces were thoroughly root planed. In experimental sites a customized barrier was formed and fitted to cover the defect. Surgical flaps were replaced slightly coronal to the cemento-enamel junction. Animals were sacrificed at 6 months and specimens processed for histologic evaluation. Histologic and histometric analyses were done using 6 micrograms step serial sections in the buccal-lingual plane, corresponding to the buccal-lingual extent of the furcation. Results were: mean total defect experimental sites 1.92 mm; control sites 1.47 mm. Mean new cementum formation experimental sites 1.36 mm (71% of initial defect); control sites 0.25 mm (17% of initial defect). Mean new bone formation experimental sites 1.42 mm (74% of initial defect); control sites 0.20 mm (14% of initial defect). Mean junctional epithelium formation experimental sites 0.42 mm (22% of initial defect); control sites 1.21 mm (82% of initial defect). Statistical analysis demonstrated significant differences in all healing parameters favoring experimental (barrier-treated) sites. In this model, regeneration (new bone, cementum, and periodontal ligament) of 71% of the original defect in experimental sites and only 14% in control sites demonstrated a response that highly favored use of the barrier.

Alveolar Bone Loss↗
PubMed2005

Periodontal regeneration in intrabony defects after application of enamel matrix proteins with guided tissue regeneration: an experimental study in dogs.

The aim of this study was to evaluate the effects of enamel matrix proteins (EMP) at the early stage of wound healing in the periodontal tissues by a combination treatment with guided tissue regeneration (GTR). Intrabony defects were produced surgically at the distal aspects of both mandibles in six beagle dogs. At 12 weeks following the surgery, the defects were exposed using a full thickness mucoperiosteal flap procedure. Subsequently, the defects were treated by the following treatments: a control group treated with GTR alone, and an experimental group treated with a combination of GTR and EMP. After one, two, four and eight weeks of the treatment, the animals were sacrificed, and sections of the tissue were stained and evaluated microscopically. After one and two weeks, the proliferating cell nuclear antigen (PCNA)-positive cell ratios of the experimental group were significantly greater than that of the control group. After 2 and 4 weeks, new bone and new cementum formation in the experimental group were significantly greater than those in the control group (P < 0.05). However, after 8 weeks, no statistical difference was found between the two groups in new bone or cementum formation. The study results suggest that a maturation of periodontal ligament cells might contribute, during the early stage of periodontal healing, to stimulate a proliferation of periodontal ligament cells.

Animals↗