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PubMed1991

Skeletal muscle regeneration in young rats is dependent on growth hormone.

Skeletal muscle fibres have a well known ability to regenerate after different kinds of injury. This study was undertaken to establish if regenerating skeletal muscle is dependent on growth hormone (GH) in the same manner as normal, growing skeletal muscle in young rats. Muscle regeneration was achieved by injection of notexin into the soleus muscle. Initial necrosis, which included all muscle fibres, was followed by a rapid and uniform regeneration throughout the muscle. Cell proliferation was estimated by scintillation counting and autoradiography of incorporated [3H]thymidine, injected intravenously 1 h before killing, 7 or 27 days after the initiation of regeneration. GH deficiency was accomplished by hypophysectomy 4 days before the [3H]thymidine injection. Cell proliferation was diminished in both regenerating and normal muscle of the hypophysectomized rats compared to control and GH-substituted rats. After 7 days of regeneration the reduction of cell proliferation seen in hypophysectomized rats was less pronounced in the regenerating than in the normal muscle. These findings demonstrate that GH plays an important role for muscle regeneration in young rats, although other substances appear to be of greater importance during the early stages of regeneration.

Animals↗
PubMed1984

Skeletal muscle regeneration after myonecrosis induced by crude venom and a myotoxin from the snake Bothrops asper (Fer-de-Lance).

Skeletal muscle regeneration was studied following injections of Bothrops asper venom and a myotoxin isolated from the crude venom. In toxin-injected muscle regeneration proceeded normally. By 4 days there were myotubes and small regenerating cells. The size of the cells increased by 1 and 2 weeks, and by 4 weeks regenerating cells were fully developed. The regenerated cells retained centrally located nuclei. The regenerative process in venom-injected muscle was not completely normal--by 1 and 2 weeks four main areas, based on the predominant cell type present, were observed in the tissue: (a) necrotic muscle cells; (b) regenerating muscle cells; (c) fibroblasts and collagen; (d) adipocytes. Furthermore, some nerve fibers were demyelinated. Samples obtained 4 weeks after venom injection showed an almost complete regeneration in many areas, whereas in other areas nests of small regenerating cells were surrounded by portions of adipose tissue and collagen. At four weeks regenerating cells in venom-injected muscle were significantly smaller than cells in toxin-injected and saline-injected muscles. There was a significant reduction in capillary/muscle cell ratio in areas of the muscle where hemorrhage and myonecrosis were present 30 min after injection of B. asper venom. Since B. asper venom drastically affects the microvasculature, it is proposed that impairment of regeneration after injection of crude venom is a consequence of diminished blood supply to some areas of the muscle.

Animals↗
PubMed1986

Skeletal muscle regeneration after myonecrosis induced by Bothrops asper (terciopelo) venom.

In order to assess the extent of regeneration, creatine kinase content of injected gastrocnemius muscle were determined at four time intervals after inoculation. Simultaneously, the diameters of regenerating fibers were measured, the wet weight of the gastrocnemius was recorded and electrophoretic patterns of muscle proteins and histology of the tissue were analyzed. Injection of crude B. asper venom caused myonecrosis and hemorrhage; in these cases regeneration was very poor, as there was only a small increase in creatine kinase content by four weeks. Histologically, large areas of fibrosis were observed, intermixed with small areas of regenerating muscle. Furthermore, the diameter of regenerating muscle cells was abnormally small, even four weeks after envenomation. In order to test the role of hemorrhage in impairment of regeneration, we also studied the effects of B. asper venom that had been incubated with a volume of antivenom that completely neutralized hemorrhagic activity, but not myotoxic activity. At 24 hr mice showed a generalized picture of myonecrosis, without hemorrhage. Afterwards, regeneration proceeded and significant increases in creatine kinase content were demonstrated at 1, 2 and 4 weeks. Also, histological observations showed the presence of many areas of regenerating muscle, intermixed with small areas of fibrosis and adipose tissue. The diameter of regenerating cells increased with time, reaching values of 25.8 microns by four weeks. Electrophoretic analyses of muscle proteins showed that muscle injected with partially neutralized venom underwent a more complete regeneration than muscle injected with crude venom.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Expression of a developmentally regulated, phosphorylated isoform of microtubule-associated protein 1B in regenerating axons of the sciatic nerve.

Monoclonal antibodies SMI-31 and 150 recognize phosphorylation epitopes on microtubule-associated protein 1B that have been shown to be developmentally down-regulated in the nervous system. We have used these antibodies to establish changes in the pattern of expression of their epitopes on microtubule-associated protein 1B in regenerating axons of the sciatic nerves in the adult mouse and rat. Immunohistochemical studies showed that, in the sciatic nerve, regenerating axons in both adult mice and rats were labelled with monoclonal antibody 150 in a proximodistal gradient which was highest at the growth cone. This is the first report of expression of a developmentally regulated, phosphorylated isoform of microtubule-associated protein 1B in regenerating axons. Immunoblotting showed that the expression of the isoform recognized by monoclonal antibody 150 is present in normal adult mouse sciatic nerve and in regenerating axons following crush or cut lesions, but was not detectable in the normal or regenerating adult rat peripheral nervous system. Regenerating axons were also labelled by monoclonal antibody SMI-31, but the labelling, unlike antibody 150 labelling, was uniform along the entire length of the axon and immunoblotting showed that it was due to recognition of neurofilament protein. We conclude that the phosphorylated isoforms of microtubule-associated protein 1B recognized by monoclonal antibody 150 that are developmentally down-regulated in the adult rat central and peripheral nervous systems and adult mouse cerebellum are maintained in the normal peripheral nervous system of the adult mouse. When peripheral axons regenerate in the adult mouse, the regenerating axons also contain these isoforms. Adult rat regenerating axons are stained by antibody 150 only in tissue sections, not in immunoblots. The maintenance of immature isoforms of microtubule-associated protein 1B in mouse peripheral axons may relate to a continual capacity for growth and remodelling. The immunohistochemical localization of the antibody 150 epitope in growth cone-like structures and sprouts in injured nerves shows that phosphorylation of microtubule-associated protein 1B is likely to be an integral part of the regenerative response. These results also show that the phosphorylation epitopes on microtubule-associated protein 1B recognized by monoclonal antibodies 150 and SMI-31 are different and that only expression of the former correlates with axonal regeneration.

Animals↗
PubMed2005

Matrix metalloproteinase expression and function during fin regeneration in zebrafish: analysis of MT1-MMP, MMP2 and TIMP2.

Matrix metalloproteinases (MMPs) play key roles in the turnover of extracellular matrix (ECM) and, thereby, function as key regulators of cell-ECM interactions during development. In spite of their importance during developmental processes, relatively little has been reported about the role of these metalloproteinases during limb development and regeneration. To approach the problem of cell-ECM interactions during limb (fin) regeneration, we have utilized zebrafish as an experimental model. Based on previous MMP cloning studies from our laboratory, the current study has focused on the expression of membrane-type 1 metalloproteinase (MT1-MMP), gelatinase A (MMP-2) and endogenous tissue inhibitor 2 of metalloproteinases (TIMP-2) during fin regeneration in adult zebrafish. In situ analysis indicated co-expression of zmt1-mmp, zmmp-2, and ztimp-2 mRNA transcripts in regenerating caudal fins. In situ gelatin-zymography confirmed the presence of active metalloproteinases in regenerating fins. zmt1-mmp, zmmp-2, and ztimp-2 mRNA transcripts were expressed in the blastema and basal epithelium during caudal fin regeneration while expression of type IV collagen [zcol-IV(a5)] transcripts (a basal lamina component) was restricted to the basal epithelium. Fin outgrowth was greatly reduced in the presence of GM6001 (an inhibitor of MMP activity) indicating the importance of these enzymes during fin regeneration. Previous studies by Itoh (EMBO, 2001) indicated that expression of a vertebrate MT1-MMP construct containing only the hemopexin-transmembrane-cytoplasmic domains (MT1HPX) resulted in blockage of MT1-MMP homophilic complex formation and subsequent inhibition of pro-MMP-2 activation. Interference with homophilic complex formation was attributed to expression of the hemopexin domain at the cell surface. Building upon these earlier findings, the current study found that ectopic expression of MT1HPX in fin regenerates inhibited the regeneration process and resulted in a reduction in cell proliferation in the blastema. Taken together, these results indicate that MMPs have an important role during fin regeneration in zebrafish.

Animals↗
PubMedDate not supplied

Lens regeneration in mammals: a review.

Lens regeneration occurs in New Zealand albino rabbits after endocapsular lens extraction, if the anterior and posterior capsules remain relatively intact. Research beginning in the 19th century showed that regeneration of the lens begins as early as 2 weeks postoperatively, depends on the size of the capsulotomy and how it has scarred, and is faster in younger animals. More recently, implantation of embryonic ectoderm at the time of lens removal has been shown to improve the growth and quality of the regenerated lenses. Lens fiber differentiation follows a process similar to embryological development with proliferation of epithelial cells along the anterior and posterior capsule, elongation of the posterior epithelial cells, and differentiation into lens fibers. Signals required for lens fiber differentiation include FGF, IGF-1, and TGF-beta. Identifying other signals, and providing these factors to the regenerating lens, could speed up lens regeneration and improve normality of the resulting structure. The regenerated lenses contain the same proteins as normal lenses, including all the major crystallins (alpha, beta, and gamma). However, regenerated lenses have typically been irregular in shape due to lack of lens growth at the site of the anterior capsulotomy and its adhesion to the posterior capsule. Sealing the capsulotomy and refilling the bag to maintain its shape seem to allow for more normal lens regeneration. Lens regeneration is a potential approach to restoring normal vision after cataract surgery. Importantly, lenses have been shown to regenerate after removal of cataracts in several mammals, and primate lenses do have regenerative capability.

Animals↗
PubMed2002

Expression of alpha7beta1 integrin splicing variants during skeletal muscle regeneration.

Integrin alpha7beta1 is a laminin receptor, both subunits of which have alternatively spliced, developmentally regulated variants. In skeletal muscle beta1 has two major splice variants of the intracellular domain (beta1A and beta1D). alpha7X1 and alpha7X2 represent variants of the alpha7 ectodomain, whereas alpha7A and alpha7B are variants of the intracellular domain. Previously we showed that during early regeneration after transection injury of muscle alpha7 integrin mediates dynamic adhesion of myofibers along their lateral aspects to the extracellular matrix. Stable attachment of myofibers to the extracellular matrix occurs during the third week after injury, when new myotendinous junctions develop at the ends of the regenerating myofibers. Now we have analyzed the relative expression of beta1A/beta1D and alpha7A/alpha7B and alpha7X1/alpha7X2 isoforms during regeneration for 2 to 56 days after transection of rat soleus muscle using reverse transcriptase-polymerase chain reaction and immunohistochemistry. During early regeneration beta1A was the predominant isoform in both the muscle and scar tissue. Expression of muscle-specific beta1D was detected in regenerating myofibers from day 4 onwards, ie, when myogenic mitotic activity began to decrease, and it became more abundant with the progression of regeneration. alpha7B isoform predominated on day 2. Thereafter, the relative expression of alpha7A transcripts increased until day 7 with the concomitant appearance of alpha7A immunoreactivity on regenerating myofibers. Finally, alpha7B again became the predominant variant in highly regenerated myofibers. Similarly as in the controls, alpha7X1 and alpha7X2 isoforms were both expressed throughout the regeneration with a peak in alpha7X1 expression on day 4 coinciding with the dynamic adhesion stage. The results suggest that during regeneration of skeletal muscle the splicing of beta1 and alpha7 integrin subunits is regulated according to functional requirements. alpha7A and alpha7X1 appear to have a specific role during the dynamic phase of adhesion, whereas alpha7B, alpha7X2, and beta1D predominate during stable adhesion.

Animals↗
PubMed1998

Functional recovery of vision in regenerated optic nerve fibers.

Retinal ganglion cells (RGCs) of adult mammals normally suffer from retrograde cell death after optic nerve section. However, with transplantation of a segment of peripheral nerve (PN), their axons can regenerate and regrow through the graft. When properly guided, the regenerated axons make functional synapses with the target cells in the superior colliculus. Two months after PN graft we studied the number and morphology of RGCs with regenerated axons in adult cats. Number of regenerated RGCs was a few percent of the total population and, among various RGC types, alpha cells revealed the greatest ability for axonal regeneration and ON-center RGCs tended to regenerate better than OFF-center cells. While dendritic field dimension of RGCs with regenerated axons was mostly preserved, their regenerated axons were thinner than normal optic axons and mostly unmyelinated. The RGCs with regenerated axons revealed normal physiological properties in response to visual stimuli, and were classifiable into Y, X or W cells. In accordance with morphological results, Y cells (morphological alpha cells) were most frequently sampled. In hamsters and rats it has been shown that the animals with reconstructed retinocollicular pathway by the PN graft reveal behavioral recovery of visual function. However, in the cat, trials are still in progress to reconstruct the retinogeniculate pathway. The present status of researches on optic nerve regeneration of adult mammals using the PN graft is reviewed, and some future directions discussed.

Action Potentials↗
PubMed1998

Irregular regeneration of hepatocytes and risk of hepatocellular carcinoma in chronic hepatitis and cirrhosis with hepatitis-C-virus infection.

BACKGROUND: Hepatocellular carcinoma (HCC) commonly develops in patients with chronic hepatitis or cirrhosis of the liver caused by hepatitis-C-virus (HCV) infection. We prospectively studied whether irregular regeneration of hepatocytes is a risk factor for HCC in these patients. METHODS: 242 patients were enrolled after liver biopsy and followed up by ultrasonographic scanning every 3 months. We examined age, sex, platelet count, the diagnosis of cirrhosis or chronic hepatitis, liver-cell dysplasia, and irregular regeneration. We classified irregular regeneration as slight or severe, based on histological expression of pleiomorphism, anisocytosis, bulging, and map-like distribution of hepatocytes. FINDINGS: 37 of 63 patients with cirrhosis and 26 of 179 with chronic hepatitis were judged to have severe irregular regeneration. HCC was diagnosed in 33 of 63 patients with cirrhosis (29 had severe irregular regeneration) and 12 of 179 patients with chronic hepatitis (11 had severe irregular regeneration) during mean follow-up of 5.5 years (SD 4.1; range 1-16). Multivariate analysis with a proportional-hazards model showed severe irregular regeneration (relative risk 15.1 [95% CI 5.6-40.7], p<0.0001) and a diagnosis of cirrhosis (3.8 [1.7-8.2], p=0.0008) to be significant risk factors for HCC. Within the diagnostic categories, irregular regeneration was also significant (cirrhosis 6.8 [2.1-21.9], p=0.0014; chronic hepatitis 28.5 [2.9-276.4], p=0.0038). INTERPRETATION: We recommend that liver biopsy to look for irregular regeneration should be done in patients with HCV-related chronic liver diseases. Those with severe irregular regeneration should be followed up carefully.

Adult↗
PubMed1999

Optic nerve regeneration after intravitreal peripheral nerve implants: trajectories of axons regrowing through the optic chiasm into the optic tracts.

We have studied axon regeneration through the optic chiasm of adult rats 30 days after prechiasmatic intracranial optic nerve crush and serial intravitreal sciatic nerve grafting on day 0 and 14 post-lesion. The experiments comprised three groups of treated rats and three groups of controls. All treated animals received intravitreal grafts either into the left eye after both left sided (unilateral) and bilateral optic nerve transection, or into both eyes after bilateral optic nerve transection. Control eyes were all sham grafted on day 0 and 14 post-lesion, and the optic nerves either unlesioned, or crushed unilaterally or bilaterally. No regeneration through the chiasm was seen in any of the lesioned control optic nerves. In all experimental groups, large numbers of axons regenerated across the optic nerve lesions ipsilateral to the grafted eyes, traversed the short distal segment of the optic nerve and invaded the chiasm without deflection. Regeneration was correlated with the absence of the mesodermal components in the scar. In all cases, axon regrowth through the chiasm appeared to establish a major crossed and a minor uncrossed projection into both optic tracts, with some aberrant growth into the contralateral optic nerve. Axons preferentially regenerated within the degenerating trajectories from their own eye, through fragmented myelin and axonal debris, and reactive astrocytes, oligodendrocytes, microglia and macrophages. In bilaterally lesioned animals, no regeneration was detected in the optic nerve of the unimplanted eye. Although astrocytes became reactive and their processes proliferated, the architecture of their intrafascicular processes was little perturbed after optic nerve transection within either the distal optic nerve segment or the chiasm. The re-establishment of a comparatively normal pattern of passage through the chiasm by regenerating axons in the adult might therefore be organised by this relatively immutable scaffold of astrocyte processes. Binocular interactions between regenerating axons from both nerves (after bilateral optic nerve transection and intravitreal grafting), and between regenerating axons and the intact transchiasmatic projections from the unlesioned eye (after unilateral optic nerve lesions and after ipsilateral grafting) may not be important in establishing the divergent trajectories, since regenerating axons behave similarly in the presence and absence of an intact projection from the other eye.

Age Factors↗
PubMed2001

Differential effects of intravitreal optic nerve and sciatic nerve grafts on the survival of retinal ganglion cells and the regeneration of their axons.

We have investigated the effects of intravitreal sciatic nerve (SN) and/or optic nerve (ON) grafts on the survival and the axonal regeneration of retinal ganglion cells (RGCs). Following transection of the ON, approximately 40% RGCs survived at 7 days post-axotomy (dpa). Results showed that the intravitreal ON graft significantly promoted the survival of RGCs at 7 dpa (39,063 vs 28,246). Intravitreal SN graft, however, did not rescue axotomized RGCs at 5, 7 or 14 dpa. Axotomized RGCs could be induced to regenerate axons along a segment of SN graft attached to the proximal stump of ON. On average, 608 axotomized RGCs were induced to regenerate axons along the attached SN graft. The presence of intravitreal SN graft promoted about 100% increase in the number of regenerating RGCs (1,227) relative to the control groups. The intravitreal ON graft, surprisingly, also induced about 100% more regenerating RGCs (1220) than in the control group. When SN and ON grafts were co-transplanted into the vitreous, about 200% more regenerating RGCs (1916) were observed than in the control group. These findings illustrated that the intravitreal ON graft rescued axotomized RGCs and enhanced the regeneration of retinal axons. This is the first report to show that ON promotes RGC axonal regeneration. The intravitreal SN graft did not rescue RGCs but promoted axonal regeneration. The differential effects of intravitreal ON and SN grafts on the survival and the RGC regeneration suggest that these might be two independently operating events.

Animals↗
PubMed2002

Central and peripheral nerve regeneration by transplantation of Schwann cells and transdifferentiated bone marrow stromal cells.

In contrast to the peripheral nervous system (PNS), little structural and functional regeneration of the central nervous system (CNS) occurs spontaneously following injury in adult mammals. The inability of the CNS to regenerate is mainly attributed to its own inhibitorial environment such as glial scar formation and the myelin sheath of oligodendrocytes. Therefore, one of the strategies to promote axonal regeneration of the CNS is to experimentally modify the environment to be similar to that of the PNS. Schwann cells are the myelinating glial cells in the PNS, and are known to play a key role in Wallerian degeneration and subsequent regeneration. Central nervous system regeneration can be elicited by Schwann cell transplantation, which provides a suitable environment for regeneration. The underlying cellular mechanism of regeneration is based upon the cooperative interactions between axons and Schwann cells involving the production of neurotrophic factors and other related molecules. Furthermore, tight and gap junctional contact between the axon and Schwann cell also mediates the molecular interaction and linking. In this review, the role of the Schwann cell during the regeneration of the sciatic (representing the PNS) and optic (representing the CNS) nerves is explained. In addition, the possibility of optic nerve reconstruction by an artificial graft of Schwann cells is also described. Finally, the application of cells not of neuronal lineage, such as bone marrow stromal cells (MSCs), in nerve regeneration is proposed. Marrow stromal cells are known as multipotential stem cells that, under specific conditions, differentiate into several kinds of cells. The strategy to transdifferentiate MSCs into the cells with a Schwann cell phenotype and the induction of sciatic and optic nerve regeneration are described.

Animals↗
PubMed1996

Stage-dependent genetically-based deformities of the regenerating newt limb from 4-nitroquinoline-N-oxide mutagenesis: potential embryonic regulation of cancer.

The effect of the mutagenic carcinogen 4-nitroquinoline-N-oxide (4NQO) on limb regeneration was studied in adult Triturus cristatus newts. Delayed limb regeneration was observed when a 10- to 15-micrograms crystal of 4NQO was implanted at the late dedifferentiation or late bud stage. Additionally, 4NQO administration at these stages caused developmental deformities in skeletal elements of the subsequent regenerates. In contrast, 4NQO implanted at the wound healing stage did not affect skeletal morphogenesis. These critical stages of limb regeneration affected by carcinogen exposure (but not other manipulations) represent mechanisms distinct from disruption of basement membrane deposition. Secondary regeneration, initiated by reamputation of the 4NQO-treated abnormal regenerates 4-5 mm proximal to the site of carcinogen implantation, produced normal regenerates, setting a limit on the diffusion distance of 4NQO in the limb. Distal reamputation through regenerates at the level of the abnormality resulted in regeneration of the original bone deformity, suggesting that the teratogenic effect of 4NQO is mediated via heritable mutational events in blastema cells. These results extend a previously published conclusion that 4-NQO is mutagenic in non-regenerative tissue to include regenerative tissue as well. However, in spite of mutagenic activity, squamous carcinomas were not induced by 4NQO exposure at any stage of regeneration. Therefore, the resistance of regenerative tissue to 4'-NQO carcinogenesis is not due to resistance to mutations, but rather to other mechanisms perhaps similar to those which regulate malignant cells in murine embryos.

4-Nitroquinoline-1-oxide↗
PubMed1999

The transitional zone and CNS regeneration.

Most nerves are attached to the neuraxis by rootlets. The CNS-PNS transitional zone (TZ) is that length of rootlet containing both central and peripheral nervous tissue. The 2 tissues are separated by a very irregular but clearly defined interface, consisting of the surface of the astrocytic tissue comprising the central component of the TZ. Central to this, myelin sheaths are formed by oligodendrocytes and the supporting tissue is astrocytic. Peripheral to it, sheaths are formed by Schwann cells which are enveloped in endoneurium. The features of transitional nodes are a composite of those of central and peripheral type. The interface is penetrated only by axons. It is absent at first. It is formed by growth of processes into the axon bundle from glial cell bodies around its perimeter. These form a barrier across the bundle which fully segregates prospectively myelinated axons. Rat spinal dorsal root TZs have been used extensively to study CNS axon regeneration. The CNS part of the TZ responds to primary afferent axon degeneration and to regenerating axons in ways which constitute a satisfactory model of the gliotic tissue response which occurs in CNS lesions. It undergoes gliosis and the gliotic TZ tissue expands distally along the root. In mature animals axons can regenerate satisfactorily through the endoneurial tubes of the root but cease growth on reaching the gliotic tissue. The general objective of experimental studies is to achieve axon regeneration from the PNS through this outgrowth and into the dorsal spinal cord. Since immature tissue has a greater capacity for regeneration than that of the adult, one approach includes the transplantation of embryonic or fetal dorsal root ganglia into the locus of an extirpated adult ganglion. Axons grow centrally from the transplanted ganglion cells and some enter the cord. Other approaches include alteration of the TZ environment to facilitate axon regeneration, for example, by the application of tropic, trophic, or other molecular factors, and also by transplantation of cultured olfactory ensheathing cells (OECs) into the TZ region. OECs, by association with growing axons, facilitate their extensive regeneration into the cord. Unusually, ventral motoneuron axons may undergo some degree of unaided CNS regeneration. When interrupted in the spinal cord white matter, some grow out to the ventral rootlet TZ and thence distally in the PNS. The DRTZ is especially useful for quantitative studies on regeneration. Since the tissue is anisometric, individual parameters such as axon numbers, axon size and glial ensheathment can be readily measured and compared in the CNS and PNS environments, thereby yielding indices of regeneration across the interface for different sets of experimental conditions.

Animals↗
PubMed2000

VEGF enhances intraneural angiogenesis and improves nerve regeneration after axotomy.

Whilst there is an increased understanding of the cell biology of nerve regeneration, it remains unclear whether there is a direct interrelationship between vascularisation and efficacy of nerve regeneration within a nerve conduit. To establish this is important as in clinical surgery peripheral nerve conduit grafting has been widely investigated as a possible alternative to the use of nerve autografts. The aim of this study was to assess whether vascular endothelial growth factor (VEGF), a highly specific endothelial cell mitogen, can enhance vascularisation and, indirectly, axonal regeneration within a silicone nerve regeneration chamber. Chambers containing VEGF (500-700 ng/ml) in a laminin-based gel (Matrigel) were inserted into 1 cm rat sciatic nerve defects and nerve regeneration examined in relation to angiogenesis between 5 and 180 d. Longitudinal sections were stained with antibodies against endothelial cells (RECA-1), axons (neurofilament) and Schwann cells (S-100) to follow the progression of vascular and neural elements. Computerised image analysis demonstrated that the addition of VEGF significantly increased blood vessel penetration within the chamber from d 5, and by d 10 this correlated with an increase of axonal regeneration and Schwann cell migration. The pattern of increased nerve regeneration due to VEGF administration was maintained up to 180 d, when myelinated axon counts were increased by 78 % compared with plain Matrigel control. Furthermore the dose-response of blood vessel regeneration to VEGF was clearly reflected in the increase of axonal regrowth and Schwann cell proliferation, indicating the close relationship between regenerating nerves and blood vessels within the chamber. Target organ reinnervation was enhanced by VEGF at 180 d as measured through the recovery of gastrocnemius muscle weights and footpad axonal terminal density, the latter showing a significant increase over controls (P < 0.05). The results demonstrate an overall relationship between increased vascularisation and enhanced nerve regeneration within an acellular conduit, and highlight the interdependence of the 2 processes.

Animals↗
PubMed2005

Lymphatic regeneration following hind limb replantation: an experimental study in the dog.

Different types of trauma to the lymphatic system can often occur, but surgical intervention can be performed only in specific cases. We report on lymphatic regeneration following limb replantation in traumatic amputations and replantation of extremities. The aim of this study was to observe the progression and reaction after surgical trauma that is similar to other kinds of trauma, both in children or adults, and to monitor the possible lymphatic regeneration. Particular attention was paid to two parameters: firstly, the physical examination of the replanted limbs by checking the post-traumatic lymphoedema, and secondly, the study of the images taken from indirect lymphangiography of the replanted limbs. Histological specimens of the surgical trauma area were also examined to reconfirm or exclude lymphatic regeneration. The study population consisted of sixteen mongrel dogs, divided into two groups of eight animals each, who underwent hind limb elective amputation and replantation combined with (group A) or without (group B) sciatic nerve division. Lymphoedema formation was followed quantitatively by measurement of the circumference of the hind limb for 21 days after replantation. Indirect lymphography, never performed before in such cases, and histopathology, were performed to evaluate and confirm lymphatic regeneration. Lymphatic regeneration after replantation of the operated hind limbs was first confirmed between 7th and 11th postoperative day by indirect lymphangiography and clinical observation of the post-traumatic lymphoedema of these limbs. The mean time of visualisation of lymphatic regeneration through lymphography was 10.12 days for group A and 9.37 days for group B. However, nerve transection had no effect on lymphatic regeneration (p = 0.46). Histopathological examination showed first evidence of lymphatic regeneration on the ninth postoperative day and a network of newly formed capillary lymphatics on the 21st postoperative day. It is concluded that lymphatic regeneration following replantation of the extremities without anastomosing of the interrupted lymph vessels, is an unquestionable fact. To achieve the best lymphatic drainage and use of the replanted extremities it is important to resect all non-vital tissues of the replantation area. Local or general infections decelerate lymphatic regeneration. Indirect lymphography with iotrolan is a reliable, easy to perform technique without complications that may be used repeatedly for confirmation and evaluation of post-traumatic lymphoedema.

Animals↗
PubMed2003

Training on a visual task improves the outcome of optic nerve regeneration.

Optic nerve regeneration in a lizard, Ctenophorus ornatus, is dysfunctional despite survival of most retinal ganglion cells and axon regeneration to the optic tectum. The regenerated retino-tectal projection at 6 months has crude topography but by 1 year is disordered; visually-elicited behavior is absent via the experimental eye. Here, we assess the influence of training on the outcome of optic nerve regeneration. Lizards were trained to catch prey presented within the monocular field of either eye. One optic nerve was then severed and visual stimulation resumed throughout regeneration. In the trained group, presentation was restricted to the eye undergoing optic nerve regeneration; for the untrained group, the unoperated eye was stimulated. Pupil responses returned in trained but not in untrained animals. At 1 year, trained animals oriented to and captured prey; untrained animals demonstrated minimal orienting and failed to capture prey. Regenerated retino-tectal projections were topographic in the trained but not in the untrained group as assessed by in vitro electrophysiological recording and by carbocyanine dye tracing. In vitro electrophysiological recording during application of neurotransmitter antagonists to the tectum revealed that the level of GABAergic inhibition was modest in trained animals but elevated in the untrained group; responses were mainly AMPA-mediated in both groups. We conclude that training improves the behavioral outcome of regeneration, presumably by stabilizing and refining the transient retino-tectal map and preventing a build-up of tectal inhibition. The results suggest that for successful central nerve regeneration to occur in mammals, it may be necessary to introduce training to complement procedures stimulating axon regeneration.

Animals↗
PubMed2003

Regenerative medicine for diseases of the head and neck: principles of in vivo regeneration.

The application of endogenous regeneration in regenerative medicine is based on the concept of inducing regeneration of damaged or lost tissues from residual tissues in situ. Therefore, endogenous regeneration is also termed in vivo regeneration as opposed to mechanisms of ex vivo regeneration which are applied, for example, in the field of tissue engineering. The basic science foundation for mechanisms of endogenous regeneration is provided by the field of regenerative biology. The ambitious vision for the application of endogenous regeneration in regenerative medicine is stimulated by investigations in the model organisms of regenerative biology, most notably hydra, planarians and urodeles. These model organisms demonstrate remarkable regenerative capabilities, which appear to be conserved over large phylogenetical stretches with convincing evidence for a homologue origin of an endogenous regenerative capability. Although the elucidation of the molecular and cellular mechanisms of these endogenous regenerative phenomena is still in its beginning, there are indications that these processes have potential to become useful for human benefit. Such indications also exist for particular applications in diseases of the head and neck region. As such epimorphic regeneration without blastema formation may be relevant to regeneration of sensorineural epithelia of the inner ear or the olphactory epithelium. Complex tissue lesions of the head and neck as they occur after trauma or tumor resections may be approached on the basis of relevant mechanisms in epimorphic regeneration with blastema formation.

Animals↗