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PubMed1983

Scanning electron microscopic observations of normal and regenerating nerve roots in the cat.

The surface morphology of normal and regenerated nerve roots was studied using correlated scanning and transmission electron microscopic methods. Nerve roots of the cauda equina were either cut and rejoined or crossed from a segment above to a segment below. Good regeneration was observed in both experimental procedures. The regenerated nerve root sheath had alterations in surface structure created by extensive growth of collagen. Despite this collagen formation, regenerated axons crossed the anastomotic site with relative ease. Surface features of the regenerated axons were similar in appearance to those of the normal axon. Schwann cells were easily recognized, as were the collagen fibers of the endoneurium, although the endoneurium was more prominent and occupied more of the interaxonal space. Macrophages were identified as round structures with a laminated surface or as a honeycomb structure. Internal features of the regenerating axons were more difficult to identify, but mitochondria and a fibrous network were observed. These studies have demonstrated the application of scanning electron microscopic methods to visualize surface structures and cells in regenerated nerve roots.

Animals↗
PubMed1989

Effect of selected denervations on glycoconjugate composition and tissue morphology during the initiation phase of limb regeneration in adult Ambystoma.

This study was undertaken to assess the effects of various quantities of neural tissue on the temporal relationship of matrix glycoconjugates to the regeneration morphology. 1) Denervation before amputation revealed that a threshold level of nervous tissue was necessary to activate a regeneration response from the tissue, i.e., appearance of regeneration-specific morphologies and glycoconjugates. 2) Denervation after amputation demonstrated that the level of neural tissue necessary to maintain these responses was below the level necessary to activate the regeneration response. If neural tissue was completely removed there was a concomitant loss of regenerate morphologies and glycoconjugates. 3) Bilateral amputation of a neurogenically intact limb and its completely denervated contralateral limb revealed that the regeneration response was a localized phenomenon during the first 30 days after amputation. After 30 days the regeneration response appeared within the previously degenerated denervating limb. The results suggest that the factors controlling the regenerative response in adult Ambystoma are large diffusible substances that can be transported by the circulation and can affect the regenerative response in remote, previously activated, tissues.

Ambystoma↗
PubMed2004

Actin fiber patterns detected by Alexafluor 488 phalloidin suggest similar cell migration in regenerating and nonregenerating rodent toes.

Although mammals do not regenerate most appendages, they are able to regenerate toetips if the amputation occurs through the nail bed. The reasons for different outcomes following amputation at different levels are not understood. It is possible that cells at regenerating and nonregenerating sites migrate from fundamentally different tissues. If so, different migratory pathways could be detected. To identify putative migrating cells, microscope slides were made from both regenerating and nonregenerating toes of rats and mice on successive days after amputation. Fluorescent-labeled phalloidin, which binds polymerized f-actin, was used to identify actin filaments and fibers. Cells containing prominent actin bundles were distinguishable from those containing diffuse fibrils and those in which visible fibers were absent. Phalloidin labeling was similar in regenerating and nonregenerating digits after amputation. As early as 2 days after amputation at either proximal or distal levels, many cells of the hypodermis adjacent to the wound became labeled with phalloidin. The number and intensity of labeled hypodermal cells containing stress fiber-like bundles increased rapidly with time, and at successive times cells were seen progressively further distally. By approximately 7 days, they occupied the wound site immediately distal to bone of both regenerating and nonregenerating digits. Most dermal cells were unlabeled and endosteal and marrow cells contained only fibrillar actin. Phalloidin labeling does not support the concept of migration from different tissues in regenerating and nonregenerating amputation sites.

Actins↗
PubMed2005

Histological examination of antler regeneration in red deer (Cervus elaphus).

Annual antler renewal presents the only case of epimorphic regeneration (de novo formation of a lost appendage distal to the level of amputation) in mammals. Epimorphic regeneration is also referred to as a blastema-based process, as blastema formation at an initial stage is the prerequisite for this type of regeneration. Therefore, antler regeneration has been claimed to take place through initial blastema formation. However, this claim has never been confirmed experimentally. The present study set out to describe systematically the progression of antler regeneration in order to make a direct histological comparison with blastema formation. The results showed that wound healing over a pedicle stump was achieved by ingrowth of full-thickness pedicle skin and resulted in formation of a scar. The growth centers for the antler main beam and brow tine were formed independently at the posterior and anterior corners of the pedicle stump, respectively. The hyperplastic perichondrium surmounting each growth center was directly formed in situ by a single type of tissue: the thickening distal pedicle periosteum, which is the derivative of initial antlerogenic periosteum. Therefore, the cells residing in the pedicle periosteum can be called antler stem cells. Antler stem cells formed each growth center by initially forming bone through intramembranous ossification, then osseocartilage through transitional ossification, and finally cartilage through endochondral ossification. There was an overlap between the establishment of antler growth centers and the completion of wound healing over the pedicle stump. Overall, our results demonstrate that antler regeneration is achieved through general wound healing- and stem cell-based process, rather than through initial blastema formation. Pedicle periosteal cells directly give rise to antlers. Histogenesis of antler regeneration may recapitulate the process of initial antler generation.

Animals↗
PubMed1979

The morphological and physiological properties of a regenerating synapse in the C.N.S. of the leech.

Regeneration of an electrical synapse between particular interneurons in the medicinal leech was traced physiologically and morphologically using intracellular recording the horseradish peroxidase (HRP) injection. The synapse between S-cell interneurons lies in the connective midway between segmental ganglia, so crushing near one ganglion severs only one S-cell's axon. The severed distal stump remains connected to the adjacent uninjured S-cell and continues for weeks to conduct impulses. The injured cell regenerates, while its uninjured "target" neuron in the next ganglion does not grow. After the sprouts of the regenerating neuron cross the crush, one or a few branches grow along the surviving distal stump toward the original synapse. After about one month when the region of original synapse has been reached, regenerating neurons form electrical junctions and stop growing. Thereafter electrical coupling improves in stages. Within two months the regenerated neuron attains full caliber, the stump degenerates and function is normal. In some instances within days or weeks of crushing, the regenerating neuron forms a basket of synapses upon its severed distal stump and then continues growing to synapse with the target. When this occurs, electrical coupling and subsequent impulse transmission between S-cells rapidly resumes. These experiments indicated that the regenerating neuron is guided to its proper synaptic target by recognizing and following its severed distal stump. Sometimes the distal stump itself becomes an intermediate synaptic target.

Animals↗
PubMed1984

A comparison of the normal and regenerated retinotectal pathways of goldfish.

This is a light and electron microscopic study of the retinotectal pathway: intact and after regeneration of the optic nerve. The spatiotemporal pattern of axonal outgrowth and termination was studied with the methods of proline autoradiography, horseradish peroxidase (HRP) labeling, and fiber degeneration. The spatial order of optic fibers in the normal and regenerated pathways was assessed by labeling small groups intraretinally with HRP and then tracing them to the tectum. The labeled fibers occupied a greater fraction of the cross section of the regenerated than the normal optic tract. At the brachial bifurcation, roughly 20% of the regenerated fibers chose the incorrect brachium vs. less than 1% of the normals. In tectum, the regenerated optic fibers reestablished fascicles in stratum opticum, but they were less orderly than in the normals. The retinal origins of the fibers in the fascicles were established by labeling individual fascicles with HRP and then, following retrograde transport, finding labeled ganglion cells in whole-mounted retinas. Labeled cells were more widely scattered over the previously axotomized retinas than over the normal ones. A similar result was obtained when HRP was applied in the tectal synaptic layer. All of these results indicate that the pathway of the regenerated optic fibers is less well ordered than the intact pathway. Both autoradiography and HRP showed that the regenerating optic fibers invaded the tectum from the rostral end, and advanced from rostral to caudal and from peripheral to central tectum, along a front roughly perpendicular to the tectal fascicles. Synapses of retinal origin were noted electron microscopically in the tectum at the same sites where autoradiography indicated that the fibers had arrived. No retinal terminals were seen where grain densities were at background levels. Fiber ingrowth and synaptogenesis apparently occurred simultaneously. The synapses were initially smaller and sparser than in normals, but were in the normal tectal strata and contacted the same classes of post synaptic elements as in normals.

Animals↗
PubMed1988

Regenerated optic fibers in goldfish reestablish a crude sectoral order in the visual pathway.

The goldfish optic pathway is regenerated after an optic nerve crush. We have examined the axonal topography of the regenerated pathway by labeling, with horseradish peroxidase (HRP), axons originating from retinal sectors or annuli. The positions of the labeled axons in the cross section of the pathway were compared to the normal and related to the factors that may influence axonal pathfinding. The positions of retinal axons in the cross section of the normal pathway are predictable from the retinal addresses of the ganglion cells described by the polar coordinates r (the distance from the optic disc) and theta (the sectoral or clockface position). The two coordinates map orthogonally onto the cross section of the pathway; r varies monotonically along one axis; theta varies along a perpendicular axis. The normal r-order, present in the nonregenerated stump of the experimental nerve, was severely degraded and perhaps lost entirely in the regenerated optic nerve, tract, and brachia. Sectoral order was also lost as the axons passed the crush site, but it was reestablished, albeit crudely, in the regenerated tract and brachia where axons tended to occupy positions appropriate to their dorsal, ventral, nasal, and temporal retinal origins. The exit sequence of the regenerated axons from the stratum opticum into the tectal neuropil was normal: temporal first, nasal last. These results suggest that the regenerating fibers followed some theta-specific cue located in the nonaxonal environment. It seems likely that the original axons probably followed the same cue. In contrast, the absence of r-order suggests that there is no r-specific cue for the regenerates to follow. It seems likely that the original r-order was a consequence of nonspecific influences--the orderly spatiotemporal growth of the retina and the existence of a permissive region for axonal growth.

Animals↗
PubMed1990

Topographic disorganization of the optic tracts following long-term optic nerve regeneration: a quantitative image analysis study.

Experiments were designed to find the degree to which regenerated optic axons occupied their previous locations in the optic tracts. Following optic nerve crush and regeneration, either the dorsal, ventral, peripheral, temporal, or nasal part of the retina was ablated. The axons of the remaining retinal ganglion cells (RGCs) were labeled with cobalt. Density of the regenerated dorsal and ventral axons in the dorsal vs. ventral optic tracts was determined digitally. In addition, we determined the density of temporal and nasal axons in the temporal vs. nasal compartments of each optic tract and the density of central axons in the central vs. peripheral compartments of both optic tracts. Regenerated axons were not distributed randomly in the optic tracts. Instead, they were slightly but, significantly biased toward growing through the tract or compartment that they had occupied previously. Still, the pathway specificity exhibited by the regenerated axons was closer to random than it was to the pathway specificity seen in normal animals. Dorsal, ventral, and central RGC axons were significantly better localized to their correct tract or compartment than were temporal or nasal RGC axons. Also, over time, dorsal and ventral axons tended to disappear from incorrectly chosen optic tracts. The slight bias toward choosing the appropriate optic tract or optic tract compartment may be enough to account for the topographic specificity of the regenerated retinotectal projection. Near-randomness of the axonal positions in the tracts argues against the presence of any specific guidance cues in the optic tracts of adult animals. Axonal density was highest in the correct compartment and diminished progressively with increasing distance into the incorrect compartment. Such a gradient of axonal density suggests that regenerating axons "drift" away from their previous positions in the optic pathways.

Animals↗
PubMed1991

The regeneration of electroreceptors in Kryptopterus.

The regeneration of ampullary electroreceptors was studied in the living catfish, Kryptopterus, by differential interference contrast optics. Electroreceptors in this transparent catfish are found, among other places, along the proximal portion of each anal fin ray, while the distal portion does not contain electroreceptors. Upon interruption of the sensory innervation, the electroreceptors disappear but regenerate when the skin is reinnervated. In this study, we tested the role of the skin and nerve in receptor regeneration with the following two experiments. First, a plug of fin containing electroreceptors was removed to determine whether electroreceptors could form in regenerated skin after the complete removal of all of the receptors within an interradial zone of the anal fin. Second, a portion of anal fin that contained electroreceptors was excised and a graft of electroreceptor-free (EF) fin was sutured in its place to determine whether epidermis that does not normally contain these receptors can be induced to form them. These grafts were compared to control grafts taken from proximal electroreceptor-containing (EC) fin. By 2 weeks following surgery, receptors were found in regenerated fin tissue and within the EC grafts. Electroreceptors also formed within most of the EF grafts. As electroreceptor regeneration does not require the presence of degenerated organs, and as electroreceptors can form in fin that normally does not contain receptors, we suggest that the formation of electroreceptors does not require old target sites and that epidermal cells can be induced to form receptors upon contact by regenerating axons. We discuss as well the factors that influence the pattern of receptor reappearance.

Animals↗
PubMed1992

Progressive morphological abnormalities observed in rat spinal motor neurons at extended intervals after axonal regeneration.

It is generally accepted that mammalian spinal motor neurons return to normal after axotomy if their regenerated axons successfully reinnervate appropriate peripheral targets. However, morphological abnormalities, recently observed in spinal motor neurons examined 1 year after nerve crush injury, raise the possibility that delayed perikaryal changes occur after regeneration is complete. In order to distinguish between chronic and progressive alterations in neurons with long-term regenerated axons, rat spinal motor neurons and dorsal root ganglion cells were examined at 5 and 10 months following unilateral sciatic nerve crush. Neurons with regenerated axons were identified by retrograde labelling with horseradish peroxidase. The structural properties of neurons ipsilateral to nerve injury were compared to those of neurons from the spinal cord and dorsal root ganglia on the contralateral side and from age-matched control rats. At 5 months postcrush, the morphology of motor and sensory neurons ipsilateral to injury was comparable to that of control cells. However, several features of the motor neurons with regenerated axons distinguished them from control motor neurons at 10 months postcrush. Mean perikaryal area of ipsilateral spinal motor neurons was larger than the means for control motor neurons (p less than .001). Ipsilateral spinal motor neurons also appeared clustered within the spinal cord and had thicker dendrites. Dorsal root ganglion cells with regenerated axons were slightly larger than control cells at 10 months postcrush but they exhibited no other morphological changes. The present findings indicate that spinal motor neurons are progressively altered after their regenerated axons have reestablished functional synapses with their peripheral targets.

Animals↗
PubMed1993

Axon dependent glial changes during optic fiber regeneration in the goldfish.

During optic fiber regeneration in the goldfish, astrocytes in the visual system undergo a number of changes. These include hypertrophy of cell processes, increased reactivity with anti-intermediate filament antisera, and expression of cytoskeletal antigens not usually seen in these cells. In the present study, I have asked how much of this response might be due to interactions of glial cells with regenerating optic axons. Animals with and without a retina (regenerating and nonregenerating animals, respectively) had their optic nerve crushed and were then examined at various postoperative times with immunohistochemical methods. Three major differences between these two groups of animals were observed. First, in nonregenerating animals the crush lesion is not repopulated by immunoreactive glial cells while in regenerating animals it is. Second, the nature of the glial hypertrophy in the optic nerve is different in regenerating and nonregenerating animals. Finally, there is marked submeningeal swelling in regenerating nerves that is absent from nonregenerating nerves. Thus, these three aspects of the cellular response to optic nerve crush in the goldfish--wound healing, optic nerve gliosis, and non-neural cellular responses--appear to depend on interactions between regenerating optic axons and astrocytes or other non-neuronal cells of the visual paths for their expression.

Animals↗
PubMed2003

Muscle regeneration in amphibians and mammals: passing the torch.

Skeletal muscle in both amphibians and mammals possesses a high regenerative capacity. In amphibians, a muscle can regenerate in two distinct ways: as a tissue component of an entire regenerating limb (epimorphic regeneration) or as an isolated entity (tissue regeneration). In the absence of epimorphic regenerative ability, mammals can regenerate muscles only by the tissue mode. This review focuses principally on the regeneration of entire muscles and covers what is known and what remains to be elucidated about fundamental mechanisms underlying muscle regeneration at this level.

Aging↗
PubMed2003

Cnidarians: an evolutionarily conserved model system for regeneration?

Cnidarians are among the simplest metazoan animals and are well known for their remarkable regeneration capacity. They can regenerate any amputated head or foot, and when dissociated into single cells, even intact animals will regenerate from reaggregates. This extensive regeneration capacity is mediated by epithelial stem cells, and it is based on the restoration of a signaling center, i.e., an organizer. Organizers secrete growth factors that act as long-range regulators in axis formation and cell differentiation. In Hydra, Wnt and TGF-beta/Bmp signaling pathways are transcriptionally up-regulated early during head regeneration and also define the Hydra head organizer created by de novo pattern formation in aggregates. The signaling molecules identified in Cnidarian regeneration also act in early embryogenesis of higher animals. We suppose that they represent a core network of molecular interactions, which could explain at least some of the mechanisms underlying regeneration in vertebrates.

Animals↗
PubMed2003

Identification of genes induced in regenerating Xenopus tadpole tails by using the differential display method.

To identify candidate gene(s) involved in the tail regeneration of Xenopus laevis tadpoles, we used the differential display method to isolate four genes (clones 1, 2, 13a, and 13b) whose expression is induced in regenerating tadpole tails. Among them, clones 13a and 13b were found to encode the Xenopus homologues of the alpha1 chain of type XVIII collagen and neuronal pentraxin I, respectively. Expression of clone 2 and neuronal pentraxin I genes increased dramatically in the blastema 3 days after amputation, whereas that for the clone 1 and type XVIII collagen genes was induced gradually after amputation. In situ hybridization revealed that the neuronal pentraxin I gene is expressed specifically in the regenerating tail epidermis but not in the normal tail epidermis or the most distal margin of the tail blastema, suggesting that it has a tissue-inductive role in tail regeneration. Expression of the four genes was induced in the limb and in the tail blastema, suggesting that they are involved in the regeneration of both organs. Finally, expression of clone 2 and neuronal pentraxin I genes was scarce during embryonic stages in comparison to the tail blastema, suggesting that their main functions are in organ regeneration. Our results demonstrate unique features of spatial and temporal gene expression patterns during Xenopus tadpole tail regeneration.

Aging↗
PubMed2004

RGD-containing peptides inhibit intestinal regeneration in the sea cucumber Holothuria glaberrima.

The sea cucumber Holothuria glaberrima is an echinoderm capable of regenerating its viscera. Previous studies from our group have shown a striking remodeling of the extracellular matrix (ECM) during intestinal regeneration. To study the role of the ECM during regeneration, we have focused on the RGD sequences present in many ECM molecules. Regenerating animals were treated with an RGDS (Arg-Gly-Asp-Ser) peptide that competes with the interaction between RGD sequence and cellular integrins. Saline and RGES (Arg-Gly-Glu-Ser) peptide injections were done as controls. The size of the regenerating intestine was determined, and the regenerating structures were analyzed by immunohistochemistry for the presence of collagen and fibronectin, as well as for muscle and other cells. The results show a delay in intestinal regeneration in animals injected with the RGDS peptide, suggesting that the ECM-integrin interaction plays an important function in the regenerative process.

Animals↗
PubMed2004

Differential tissue development during embryogenesis and regeneration in an Annelid.

The fragmenting potworm Enchytraeus japonensis (Oligochaeta, Annelida) reproduces asexually by dividing the body into several fragments that then regenerate to complete individuals in 4-5 days. Such large-scale regeneration, however, occurs only in some invertebrates. To better our understanding of why regeneration is so limited in many animals, despite their ability to undergo embryonic development from the single cell of a fertilized egg, comparisons were made between regeneration and embryonic development of E. japonensis by using two methods: histochemistry for alkaline phosphatase (ALP) and immunohistochemistry with an antibody against acetylated tubulin that visualizes nervous system development. The analyses revealed that both ALP expression patterns and central nervous system development differ between embryogenesis and the regeneration, suggesting that regeneration is not a simple reiteration of embryogenesis but involves different regulatory mechanisms. The study provides a basis for the elucidation of mechanisms that are unique and crucial to regeneration.

Alkaline Phosphatase↗
PubMed2005

Muscle formation in regenerating Xenopus froglet limb.

A spike, a resultant regenerate made after amputation of a Xenopus froglet limb, has no muscle tissue. This muscle-less phenotype was analyzed by molecular approaches, and the results of analysis revealed that the spike expresses no myosin heavy chain or Pax7, suggesting that neither mature muscle tissue nor satellite cells exist in the spike. The regenerating blastema in the froglet limb lacked some myogenesis-related marker genes, myoD and myf5, but allowed implanted muscle precursor cells to survive and differentiate into myofiber. Implantation of hepatocyte growth factor (HGF) -releasing cell aggregates rescued this muscle-less phenotype and induced muscle regeneration in Xenopus froglet limb regenerates. These results suggest that failure of regeneration of muscle is due to a disturbance of the early steps of myogenesis under a molecular cascade mediated by HGF/c-met. Improvement of muscle regeneration in the Xenopus adult limb that we report here for the first time will give us important insights into epimorphic tissue regeneration in amphibians and other vertebrates.

Amputation, Surgical↗
PubMed2005

Expression of heat-shock protein 70 during limb development and regeneration in the axolotl.

Urodele amphibians (e.g., axolotls) have the unique ability, among vertebrates, to regenerate perfectly many parts of their body after amputation. The limb has been the most widely studied regenerating structure in these organisms and provides an ideal model in which to understand how vertebrates can regenerate complex tissues. The present study focuses on Hsp-70, a member of the stress-related heat-shock protein family. This protein is normally induced after a stress or trauma such as heat-shock, ultraviolet irradiation, or wounding. Thus, studying its expression during axolotl limb regeneration, a response to an important traumatic event (amputation), is of great interest to further understand how the regenerative process is mediated. Using molecular biology and biochemical techniques, we have characterized both the spatiotemporal and quantitative expression patterns of Hsp-70 in axolotl development and regeneration. Our results show that Hsp-70 is expressed and regulated during axolotl development as in other vertebrates. Our data also demonstrate an up-regulation of the RNA transcript for Hsp-70 during limb regeneration as early as 24 hr after amputation that is maintained up to early differentiation. We also demonstrate a similar pattern of expression for the protein during regeneration. Finally, we show that axolotl Hsp-70 is induced threefold after heat-shock as observed in other vertebrates.

Ambystoma mexicanum↗