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PubMed2004

Functional, electrophysiologic, and morphometric evaluation of nerve regeneration from coaptation on regenerated nerve fibers: experimental study in rabbits.

The importance of a sufficient number of nerve fibers at a proximal coaptation site is indisputable for the successful repair of nerves; however, the quality of nerve fibers required at this site has yet to be defined. The present study deals with the question of whether it is necessary to trim nerves back to unaffected neuronal tissue or whether the coaptation on recently regenerated nerve fibers, commonly believed to produce a poor quality of repair can, in fact, produce adequate nerve regeneration. Twenty New Zealand White rabbits received a standardized crush lesion on the peroneal nerves of both hind legs. Four weeks later, the nerves of the left hind legs (n = 20) were transected 10 mm distal to the previous crush lesion and coapted to the freshly regenerated nerve fibers. For comparison, on 10 right hind legs, the nerves were transected at the site of previous crushing (Group A, superimposition) or 10 mm proximal to the site of crushing on unscathed nerve fibers (Group B). Eleven weeks later, the quality of nerve regeneration was assessed by the toe-spreading reflex, electrophysiologic data, muscle weight, and histomorphologic evaluation. In the animals of Group A, the quality of nerve regeneration following coaptation on the regrown axons did not differ in any of the examined parameters from the quality of nerve fibers outgrown from the site of the superimposed lesion. Both lesions led to a completely functional reinnervation. Also in Group B, nerve action potential recording and histologic data on both sides did not reveal a significant difference between the number and maturation of nerve fibers equidistant from the suture site, shortly before muscle entrance. With this coaptation model, it could be demonstrated in the peroneal nerve of rabbits, that coaptation to recently regenerated nerve fibers leads to a significant functional regeneration.

Anastomosis, Surgical↗
PubMed1997

Effects of octreotide on liver regeneration and tumour growth in the regenerating liver.

The ability of the liver to regenerate following resection is remarkable. However, there is evidence to suggest that tumour growth within the regenerating liver is significantly increased. As octreotide (a synthetic analogue of somatostatin) inhibits the growth and development of hepatic tumour in rats, we have investigated its effects on liver regeneration, liver blood flow, hepatic reticuloendothelial system activity and tumour growth in the rat following partial hepatectomy (PH). Octreotide significantly inhibited liver regeneration in the rat 1 and 2 weeks following PH when compared with controls (regeneration index: 1.0 and 1.14 cf. 1.14 and 1.4, respectively). There was no significant difference in hepatic arterial or portal venous blood flow following PH in control or octreotide-treated rats. However, portal pressure was significantly reduced in octreotide-treated rats. Hepatic reticuloendothelial system activity was significantly increased in octreotide-treated rats compared with control animals 1 and 2 weeks after hepatectomy (uptake of radiolabelled technetium-99m albumin colloid: 2.2 and 3.9 cf. 1.6 and 1.9). The growth of both HSN (fibrosarcoma) and K12-Tr (colonic adenocarcinoma) cells in the regenerating liver was significantly decreased by octreotide treatment compared with controls (median percentage hepatic replacement: HSN control 71.3%, Octreotide 8.4%, K12-Tr Control 38.3%, Octreotide 4.5%). The results of the present study demonstrate that octreotide inhibits both liver regeneration and tumour growth following PH, possibly via a similar mechanism.

Animals↗
PubMed1991

Bone regeneration using the principle of guided tissue regeneration.

The biological principle of "guided tissue regeneration" (GTR) was developed for regenerating periodontal tissues, lost as a result of periodontal disease. This principle was based on the hypothesis that non-desirable types of tissue cells can be prevented from migrating into a wound by means of a membrane barrier and at the same time giving preference to those particular cells to repopulate the wound, which have the capacity to regenerate the desired type of tissue. This principle may have its application in many areas of surgery, aimed at regeneration of lost tissues. One such area is osseous surgery aimed at bone regeneration. In the present paper, a series of experiments in laboratory animals using the method of GTR for regeneration of various types of bone defects are presented as well as examples of application in humans for regeneration of jaw bone defects in conjunction with the placement of dental implants.

Alveolar Process↗
PubMed1998

Axonal regeneration in severed peripheral facial nerve of the rabbit: relation of the number of axonal regenerates to behavioral and evoked muscle activity.

The minimum number of regenerating facial nerve myelinated motor axons that are required to innervate and activate the mimetic musculature is not known. We compare rabbit facial nerve regeneration following complete transectional injuries of the buccal division to the evoked and behavioral muscle activities of the quadratus labii superioris muscle of the rabbit in three experimental models: end-to-end direct anastomosis (N = 4), 8-mm autologous nerve grafts (N = 8), and 10-mm silicone chamber implants (N = 40). Data are presented as total numbers of regenerating myelinated axons that traverse the surgical repair and innervate the fascicles of the transected distal nerve stump, as well as the percentage of regenerating neurites, as compared to the preoperative normal controls. Five weeks after neural repair, direct end-to-end anastomosis regained more myelinated axons across the reconstructed defect (2,632 +/- 1,232; 67%) than silicone tube implants (2,006 +/- 445; 51%) or autologous cable graft repairs (1,660 +/- 1,169; 42%). However, only a small percentage of myelinated fibers innervated the intrafascicular region of the distal transected neural stump in direct anastomosis (948 +/- 168; 24%), silicone tube implants (670 +/- 275; 17%), or autologous nerve grafts (445 +/- 120; 12%) in rabbits that regained evoked and behavioral mimetic muscle activity. All rabbits with direct anastomosis and neural cable grafts regained motor activity, despite the fact that 66% of regenerating motor neurites in cable graft repairs and 54% in direct anastomosis were collateral sprouts that did not contribute to effective muscle activity. In 17 rabbits with neural regenerates within the silicone tube implants that did not regain mimetic activity, the mean number of regenerating myelinated motor axons across the defect was 504 +/- 419 (13%), and the mean number of axons that innervated the distal transected nerve stump fascicles was 277 +/- 128 (7%). Therefore, the minimal number of motor axons that is required to activate the quadratus labii superioris muscle is 12% of the original motor axon population of the normal buccal nerve division.

Anastomosis, Surgical↗
PubMed1996

Nerve dependency of regeneration: the role of Distal-less and FGF signaling in amphibian limb regeneration.

Dlx-3, a homolog of Drosophila Dll, has been isolated from an axolotl blastema cDNA library, and its expression in developing and regenerating limbs characterized. The normal expression pattern, and the changes that occur during experimental treatments, indicate a correlation between Dlx-3 expression and the establishment of the outgrowth-permitting epidermis. Dlx-3 is expressed at high levels in a distal-to-proximal gradient in the epidermis of developing limb buds, and is upregulated in the apical ectodermal cap (AEC) during limb regeneration. Expression is maximal at the late bud stage of regeneration, coincident with the transition from the early phase of nerve dependency to the later phase of nerve independence. Dlx-3 expression in the epidermis is rapidly downregulated by denervation during the nerve-dependent phase and is unaffected by denervation during the nerve-independent phase. We investigated this relationship between nerves and Dlx-3 expression by implanting FGF-2 beads into regenerates that had been denervated at a nerve-dependent stage. Dlx-3 expression was maintained by FGF-2 after denervation, and regeneration progressed to completion. In addition, we detected FGF-2 protein in the AEC and in nerves, and observed that the level of expression in both tissues decreases dramatically in response to denervation. We conclude that both limb development and regeneration require a permissive epidermis, characterized by Dlx-3 and FGF expression, both of which are maintained by FGF through an autocrine loop. The transformation of the limb epidermis into a functional AEC that produces and responds to FGF autocatalytically, is presumed to be induced by FGF. Since nerves appear to be a source of this priming FGF, it is possible that a member of the FGF family of growth factors is the elusive neurotrophic factor of limb regeneration.

Ambystoma↗
PubMed2002

Role of macrophage migration inhibitory factor (MIF) in peripheral nerve regeneration: anti-MIF antibody induces delay of nerve regeneration and the apoptosis of Schwann cells.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pluripotent cytokine involved in inflammation and immune responses as well as in cell growth. Although we previously demonstrated the presence of MIF in peripheral nerves, and MIF mRNA expression was up-regulated after axotomy, the role of MIF in nerve injury and regeneration has not been evaluated. MATERIALS AND METHODS: To examine the potential role of MIF in nerve regeneration, we locally administered an anti-MIF polyclonal antibody into regenerating rat sciatic nerves using the silicone chamber model. The effect of the anti-MIF antibody on nerve regeneration was evaluated using an axonal reflex test. In addition, we carried out a terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) assay and immunohistochemical analysis of the damaged nerve segments with regard to apoptosis-related proteins such as p53 to evaluate the effects of anti- MIF antibodies on apoptosis during the regeneration process. RESULTS: The regeneration length of the nerve in the anti-MIF antibody-treated group was significantly shorter than that in the non-immune rabbit IgG-treated group at weeks 2, 4 and 6 after surgery. TUNEL assay showed that a large number of apoptotic cells, mostly Schwann cells, were observed in the intratubal and distal nerve segments at weeks 4 and 6 after surgery by the anti-MIF antibody treatment. Consistent with these results, Ki-67-positive cells were significantly decreased by the anti-MIF antibody treatment. Immunohistochemical analyses revealed that p53 and, to a lesser extent, Fas were more up-regulated in the anti-MIF antibody-treated nerves than in the controls. CONCLUSION: Taken together, these results suggest that MIF plays an important role in acceleration of peripheral nerve regeneration and in prevention of Schwann cell apoptosis, mainly through overcoming the apoptotic effect of p53.

Animals↗
PubMed1990

[Muscle regeneration in mdx mouse, and a trial of normal myoblast transfer into regenerating dystrophic muscle].

The most ideal therapeutic trial on Duchenne muscular dystrophy (DMD) is a transfer of normal myoblasts into dystrophic muscle which has been attempted on animal models in several institutes. In the process of muscle regeneration, the transferred normal myoblasts are expected to incorporate into the regenerating fibers in host dystrophic mouse. To know the capacity of muscle regeneration in dystrophic muscle, we compared the regenerating process of the normal muscle with that of the dystrophic muscle after myonecrosis induced by 0.25% bupivacaine hydrochloride (BPVC) chronologically. In the present study, C57BL/10ScSn-mdx (mdx) mouse was used as an animal model of DMD and C57BL/10ScSn (B10) mouse as a control. There was no definite difference in the behavior of muscle fiber regeneration between normal and dystrophic muscles. The dystrophic muscle regenerated rapidly at the similar tempo to the normal as to their size and fiber type differentiation. The variation in fiber size diameter of dystrophic muscle, however, was more obvious than that of normal. To promote successful myoblast transfer from B10 mouse into dystrophic mdx mouse at higher ratio, cultured normal myoblasts were transferred into the regenerating dystrophic muscle on the first and the second day after myonecrosis induced by BPVC. Two weeks after the myoblast injection, the muscles were examined with immunohistochemical stain using anti dystrophin antibody. Although dystrophin-positive fibers appeared in dystrophic muscle, the positive fibers were unexpectedly small in number (3.86 +/- 1.50%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Regeneration and pattern formation in planarians. I. The pattern of mitosis in anterior and posterior regeneration in Dugesia (G) tigrina, and a new proposal for blastema formation.

Mitotic activity during regeneration in the planarian Dugesia (G) tigrina shows a biphasic pattern, with a first maximum at 4-12 h, a second and higher maximum at 2-4 days, and a relative minimum in between. The first peak is mainly due to pre-existing G2 cells entering mitosis shortly after cutting, whereas the second maximum is due to cells that divide after going through the S period from the onset of regeneration. From a spatial point of view, the highest mitotic values are found in stump (postblastema) regions near the wound (0-300 micron), though regions far from it also show increased mitotic values but always lower overall values. As regeneration continues the postblastema maximum shifts slightly to more proximal regions. In contrast, no mitosis has been found within the blastema, even though the number of blastema cells increases steadily during regeneration. The results suggest that blastema in planarians forms through an early accumulation of undifferentiated cells from the stump to the base of blastema. The results obtained demonstrate that blastema formation in planarians occurs through mechanisms somewhat different to those shown to occur in the classical epimorphic models of regeneration (Annelida, Insecta, Amphibia), and suggest that planarian regeneration could represent an intermediate stage between morphallactic and epimorphic modalities of regeneration.

Animals↗
PubMed2001

Polyamines as biomarkers for plant regeneration capacity: improvement of regeneration by modulation of polyamine metabolism in different genotypes of indica rice.

The importance of cellular polyamine (PA) levels and the ratio of putrescine (Put) to spermidine (Spd) for plant regeneration ability via somatic embryogenesis in several commercially grown indica rice varieties is reported here. The genotypes namely NDR-624, IR-20, IR-36, BJ-1 (having Put:Spd ratio approximately 2.3) showed superior plant regeneration while KL, PB-1 and TN-1 (having Put:Spd ratio approximately 3.8) showed moderate plant regeneration ability. The genotypes namely HS, Bindli, DV-85, ACB-72, IR-64 and IR-72 (having Put:Spd ratio approximately 5.0) showed poor plant regeneration ability. In contrast KH-7 (Put:Spd ratio approximately 10.0) showed no response at all. Favorable modification of cellular PA titers and their Put:Spd ratio by the addition of exogenous PAs (Put, Spd) or their biosynthesis inhibitor, difluoromethylarginine (DFMA) led to the induction/promotion of plant regeneration in poorly responding genotypes. These results showed a close relationship between cellular PA levels and their Put:Spd ratio with in vitro morphogenetic capacity in indica rice and suggest that the cellular PAs and Put:Spd ratios are important determinants (biomarkers) of plant regeneration ability in indica rice, and the improvement/induction of plant regeneration in morphogenetically poor and recalcitrant species could be achieved by modulating PA metabolism.

Journal Article↗
PubMed2000

Plastic changes and nitric oxide synthase induction in neurons which innervate the regenerated tail of the lizard Gekko gecko. II. The response of dorsal root ganglion cells to tail amputation and regeneration.

The lizard tail regenerates after amputation, which severs the spinal cord and spinal nerves. Dorsal root ganglia (DRGs) do not regenerate in the regrowing tail, which is innervated by DRGs rostral to the amputation. With Nissl staining, NADPH-diaphorase histochemistry and nitric oxide synthase (NOS) immunohistochemistry, we investigated NOS expression and its relationship with structural changes in DRG neurons of caudotomized lizards. First, by horseradish peroxidase retrograde tracing we here provided evidence that the sensory innervation of the regenerated tail derives only from the three pairs of DRGs rostral to the amputation plane. These ganglia were then analyzed in control animals with original intact tail, at 5, 15 and 30 days after caudotomy, and at 8 months in lizards with mature regenerates. Caudotomy elicited in DRG neurons marked hypertrophy that persisted after tail regeneration. In control ganglia, most neurons were lightly NADPH-diaphorase-positive, a few were unstained or intensely stained. Tail transection elicited marked staining up-regulation, and an increase in the proportion of intensely positive neurons. The staining intensity peaked in DRG neurons at 15 days and was still significantly increased in respect to controls several months after complete tail regeneration. NOS immunoreactivity in DRGs matched the histochemical findings. NADPH-diaphorase positivity was also enhanced in the dorsal horn superficial laminae of the corresponding spinal segments. We demonstrate that transection of the lizard spinal nerves, provoked by tail loss, elicits in the axotomized primary sensory neurons marked NOS enhancement, which accompanies axon elongation in the regrowing tail and persists after the end of this process.

Amputation, Surgical↗
PubMed2003

Periodontal repair in dogs: a bioabsorbable calcium carbonate coral implant enhances space provision for alveolar bone regeneration in conjunction with guided tissue regeneration.

BACKGROUND: Collapse or compression of a barrier device into a periodontal defect or onto the root surface compromises outcomes following guided tissue regeneration (GTR). Bone biomaterials have been suggested to support regeneration of alveolar bone and to improve space provision with GTR devices. The objective of this study was to evaluate space provision, alveolar bone, and cementum regeneration following use of a bioabsorbable, calcium carbonate biomaterial in conjunction with GTR. METHODS: Routine, critical size, 5 to 6 mm, supraalveolar, periodontal defects were created in 5 young adult beagle dogs. Alternate jaw quadrants in consecutive animals received GTR and the coral biomaterial (cGTR) or GTR alone. The animals were euthanized 4 weeks postsurgery and tissue blocks processed for histometric analysis. RESULTS: The coral implant particles were surrounded by newly-formed bone or immersed in connective tissue and appeared to resorb and be replaced by bone. There was limited, if any, appreciable cementum regeneration. Space provision was enhanced in cGTR compared to GTR sites (6.1 +/- 1.6 versus 2.4 +/- 0.8 mm2; P<0.05). Bone regeneration (height) was significantly increased in cGTR compared to GTR sites averaging 1.9 +/- 0.6 and 1.2 +/- 0.6 mm, respectively (P<0.05). Bone regeneration (area) was 2-fold greater in cGTR sites compared to the GTR control (3.3 +/- 1.8 versus 1.4 +/- 0.5 mm2), however the difference was not statistically significant (P>0.05). CONCLUSIONS: The coral implant significantly enhanced space provision for GTR while alveolar bone formation appeared to be enhanced by its use. Increased healing intervals are needed to fully understand the biologic value of the coral implant as an adjunct to GTR.

Absorbable Implants↗
PubMed1988

Staining of regenerated optic arbors in goldfish tectum: progressive changes in immature arbors and a comparison of mature regenerated arbors with normal arbors.

Individual optic arbors, normal and regenerated, were stained via anterograde transport of HRP and viewed in tectal whole mounts. Camera lucida drawings were made of 119 normal optic arbors and of 242 regenerated arbors from fish 2 weeks to 14 months postcrush. These arbors were analyzed for axonal trajectory, spatial extent in the horizontal plane, degree of branching, number of branch endings, average depth, and degree of stratification. Normal optic arbors ranged in size from roughly 100 to 400 microns across in a continuous distribution, had an average of 20 branch endings with average of fifth-order branching, and were highly stratified into one of three planes within the major optic lamina (SO-SFGS). Small arbors arising from fine-caliber axons terminated in the most superficial plane of SO-SFGS; large arbors from coarse axons terminated in the superficial and middle planes; and medium arbors from medium-caliber axons terminated in the middle and deep planes of SO-SFGS, as well as deeper in the central gray and deep white layers. Arbors from central tectum tended to be much more tightly stratified than those in the periphery. No other differences between central and peripheral arbors were noted. Mature regenerated arbors (five months or more postcrush) were normal in their number of branch endings, order of branching, and depth of termination. Their branches covered a wider area of tectum, partially because of their early branching and abnormal trajectories of branches. Axonal trajectories were often abnormal with U-turns and tortuos paths. Fine-, medium-, and coarse-caliber axons were again present and gave rise to small, medium, and large arbors at roughly the same depths as in the normals. There was frequently a lack of stratification in the medium and large arbors, which spanned much greater depths than normal. Overall, however, regenerates reestablished nearly normal morphology except for axonal trajectory and stratification. Early in regeneration, the arbors went through a series of changes. At 2 weeks postcrush, regenerated axons had grown branches over a wider-than-normal extent of tectum, though they were sparsely branched and often tipped with growth cones. At 3 weeks, the branches were more numerous and covered a still wider extent (average of five times normal), many covering more than half the tectal length or width. At 4-5 weeks smaller arbors predominated, although a few enlarged arbors were present for up to 8 weeks. Additional small changes occurred beyond 8 weeks as the arbors became progressively more normal in appearance.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2004

Early fin primordia of zebrafish larvae regenerate by a similar growth control mechanism with adult regeneration.

Some vertebrate species, including urodele amphibians and teleost fish, have the remarkable ability of regenerating lost body parts. Regeneration studies have been focused on adult tissues, because it is unclear whether or not the repairs of injured tissues during early developmental stages have the same molecular base as that of adult regeneration. Here, we present evidence that a similar cellular and molecular mechanism to adult regeneration operates in the repair process of early zebrafish fin primordia, which are composed of epithelial and mesenchymal cells. We show that larval fin repair occurs through the formation of wound epithelium and blastema-like proliferating cells. Cell proliferation is first induced in the distal-most region and propagates to more proximal regions, as in adult regeneration. We also show that fibroblast growth factor signaling helps induce cell division. Our results suggest that the regeneration machinery directing cell proliferation in response to injury may exist from the early developmental stages.

Age Factors↗
PubMed1995

Nerve regenerating effect of short-course administration of cyclosporine after fresh peripheral nerve allotransplantation in the rat: comparison of nerve regeneration using different forms of donor nerve allografts.

There is almost universal agreement that if cyclosporine (CsA), which is a potent immunosuppressant, is temporarily administered after surgery, regenerated axons will be maintained even after withdrawal of CsA following peripheral nerve allotransplantation. Thus, this experimental study was conducted to investigate whether a difference in donor nerve form, including thickness and length, influences nerve regeneration after withdrawal of immunosuppression with CsA. The findings suggest that as a result of immunosuppression with CsA, large-diameter nerve grafts are better able to induce nerve regeneration than small-diameter grafts, and after withdrawal of the immunosuppressant, thick nerve grafts are also better able to preserve regenerated axons against the rejection reaction than thin grafts. With regard to the length of the grafted nerve, short nerve allografts yield higher axon counts than long ones, the same as with autografts. The best way to induce nerve regeneration appears to be to transplant a short, thick nerve allograft, which is definitely capable of inducing many regenerated axons.

Animals↗
PubMed1988

Regeneration of goldfish retina: rod precursors are a likely source of regenerated cells.

This study describes regeneration of the neural retina in juvenile goldfish. The retina was destroyed with an intraocular injection of ouabain, a technique introduced by Wolburg and colleagues (Maier and Wolburg, 1979; Kurz-Isler and Wolburg, 1982). We confirmed their observation that the level of damage produced by the toxin was graded, in that neurons in the inner retinal layers were preferentially destroyed, and only in the more severely affected retinas were cells in the outer nuclear layer (i.e., photoreceptor cells) damaged. Evidence of retinal regeneration could be seen beginning about 2 weeks after the injection of ouabain. In contrast to previous studies (Maier and Wolburg, 1979), we found that regeneration took place only in those retinas in which photoreceptors had been destroyed. In cases in which the outer nuclear layer was spared, no regeneration of inner layers occurred, even after 6 months. Thymidine autoradiography was used to document the regeneration of new retinal neurons and to show that rod precursors, like other dividing cells, were not destroyed by the ouabain, but in contrast showed an increased mitotic activity. Regeneration did not proceed uniformly, but was initiated at neurogenic foci scattered across the retina. These foci consisted of clusters of dividing neuroepithelial-like cells. The evidence is consistent with the proposal that these cells were derived from rod precursors. These results imply that rod precursors are capable of a wider range of developmental fates than they normally express.

Animals↗
PubMed2000

Laminin alpha4 and integrin alpha6 are upregulated in regenerating dy/dy skeletal muscle: comparative expression of laminin and integrin isoforms in muscles regenerating after crush injury.

The expression of laminin isoforms and laminin-binding integrin receptors known to occur in muscle was investigated during myogenic regeneration after crush injury. Comparisons were made between dystrophic 129ReJ dy/dy mice, which have reduced laminin alpha2 expression, and their normal littermates. The overall histological pattern of regeneration after crush injury was similar in dy/dy and control muscle, but proceeded faster in dy/dy mice. In vitro studies revealed a greater yield of mononuclear cells extracted from dy/dy muscle and a reduced proportion of desmin-positive cells upon in vitro cultivation, reflecting the presence of inflammatory cells and "preactivated" myoblasts due to ongoing regenerative processes within the endogenous dystrophic lesions. Laminin alpha1 was not detectable in skeletal muscle. Laminin alpha2 was present in basement membranes of mature myofibers and newly formed myotubes in control and dy/dy muscles, albeit weaker in dy/dy. Laminin alpha2-negative myogenic cells were detected in dy/dy and control muscle, suggesting the involvement of other laminin alpha chains in early myogenic differentiation, such as laminin alpha4 and alpha5 which were both transiently expressed in basement membranes of newly formed myotubes of dy/dy and control mice. Integrin beta1 was expressed on endothelial cells, muscle fibers, and peripheral nerves in uninjured muscle and broadened after crush injury to the interstitium where it occurred on myogenic and nonmyogenic cells. Integrin alpha3 was not expressed in uninjured or regenerating muscle, while integrin alpha6 was expressed mainly on endothelial cells and peripheral nerves in uninjured muscle. Upon crush injury integrin alpha6 increased in the interstitium mainly on nonmyogenic cells, including infiltrating leukocytes, endothelial cells, and fibroblasts. In dy/dy muscle, integrin alpha6 occurred on some newly formed myotubes. Integrin alpha7 was expressed on muscle fibers at the myotendinous junction and showed weak and irregular expression on muscle fibers. After crush injury, integrin alpha7 expression extended to the newly formed myotubes and some myoblasts. However, many myoblasts and newly formed myotubes were integrin alpha7 negative. No marked difference was observed in integrin alpha7 expression between dy/dy and control muscle, either uninjured or after crush injury. Only laminin alpha4 and integrin alpha6 expression patterns were notably different between dy/dy and control muscle. Expression of both molecules was more extensive in dy/dy muscle, especially in the interstitium of regenerating areas and on newly formed myotubes. In view of the faster myogenic regeneration observed in dy/dy mice, the data suggest that laminin alpha4 and integrin alpha6 support myogenic regeneration. However, whether these accelerated myogenic effects are a direct consequence of the reduced laminin alpha2 expression in dy/dy mice, or an accentuation of the ongoing regenerative events in focal lesions in the muscle, requires further investigation.

Animals↗
PubMed2006

Involvement of the tyrosine phosphatase early gene of liver regeneration (PRL-1) in cell cycle and in liver regeneration and fibrosis effect of halofuginone.

Tyrosine phosphatase PRL-1 is one of the immediate-early genes up-regulated during liver regeneration and is apparently involved in cell proliferation. Previously, we have demonstrated that halofuginone, an inhibitor of collagen type I synthesis, prevents liver fibrosis and improves cirrhotic liver regeneration. In this study, we evaluated the effect of halofuginone on PRL-1 expression, its cellular localization in vitro and during liver regeneration, and fibrosis progression in vivo. In culture, halofuginone increased PRL-1 expression in primary rat hepatocytes and in hepatocellular carcinoma (HCC) cell lines, the former being more sensitive to halofuginone. The halofuginone-dependent increase in PRL-1 gene expression was correlated with an increase in the transcription factor early growth response-1 (Egr-1) and inversely correlated with the inhibition of cell proliferation. Halofuginone arrested HepG2 and Huh7 cell lines at the G1 phase, whereas Hep3B cells were arrested at G2/M, probably because of a reduction in the synthesis of cyclins D1 and B1 in all HCC cells and increased cyclin A in Hep3B cells. Halofuginone also affected the PRL-1 sub-cellular localization that was cell-cycle-dependent. In addition, halofuginone augmented PRL-1 expression in the remnant liver after partial hepatectomy and in chemically induced fibrosis in rats; this was accompanied by increased expression of insulin-like growth factor binding protein 1 (IGFBP-1), another immediate-early gene of regeneration. The regulation of the expression of the early genes of regeneration such as PRL-1 and IGFBP-1 is thus part of the mode of action of halofuginone and results in the prevention of liver fibrosis and improved cirrhotic liver regeneration.

Animals↗
PubMed1982

Tropism in nerve regeneration in vivo. Attraction of regenerating axons by diffusible factors derived from cells in distal nerve stumps of transected peripheral nerves.

We re-examined the hypothesis of Cajal3, later refuted by Weiss and Taylor20, that cells in distal stumps of transected peripheral nerves exert an attractive (tropic) effect on regenerating axons. This question was re-assessed in vivo using surgical materials and assay procedures not available to those workers. Proximal stumps of transected rat sciatic or cat peroneal nerves were inserted into the single inlet end of a hollow, Y-shaped Silastic implant. Regenerating axons were provided with alternative targets consisting of a vacant arm vs one occupied by a sciatic nerve graft (rat), or a tibial (Tout) vs peroneal (Pout) distal nerve stump (cat). In some cases Pout was rendered metabolically compromised relative to Tout by exposing the former to dry ice and inhibitors of DNA and RNA synthesis. At 4.5 or 6 weeks postoperatively, the number of regenerating axons in each fork of the implant was assessed by morphometric analysis (total number of non-myelinated and myelinated axons greater than 1 micron in diameter at 4.5 weeks, and total number of myelinated axons at 6 weeks postoperatively), or by quantification of an axonally transported label. Rat sciatic nerve fibers exclusively regenerated toward the nerve graft, suggesting the existence of a neurotropic lure. In cats, morphometric analysis revealed a 10-(4.5 week) and 6-fold (6 week) greater number of axons growing towards untreated Tout vs treated Pout. When both distal stumps were untreated, more axons were seen in forks leading to Pout. Analysis of transported label confirmed the preferential growth of axons towards untreated Tout vs treated Pout for both motor and sensory axons. In separate experiments, Nuclepore filters (0.2 microns, pore size) were inserted between distal nerve stumps and outlet ends of Silastic implants. Preferential regeneration toward untreated stumps was observed if the distance between proximal and distal nerve stumps was equal to but not greater than 4-5 mm. These results suggest that peripheral nerve fiber regeneration in vivo can be directed by cells in distal stumps of transected nerves, and that this effect can be mediated over distances of several millimeters via diffusible factors.

Animals↗