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PubMed1998

Developmentally regulated expression of cytochrome-c oxidase isoforms in regenerating rat skeletal muscle.

The developmental expression of tissue-specific isoforms of cytochrome-c oxidase (COX) subunit VIII [heart (COX VIII-H) and liver (COX VIII-L)] and the influence of innervation were examined in regenerating fast [extensor digitorum longus (EDL)] and slow (soleus) muscles. In adult muscles, COX VIII-H was the predominant isoform. The COX VIII-L mRNA was expressed 3 days after induction of regeneration, and it progressively decreased after 7, 10, 14, and 30 days of regeneration in both muscles. In contrast, the expression of COX VIII-H mRNA accumulated as myogenesis proceeded to the myotube stage between 7 and 10 days of regeneration and progressively increased to near control levels by 30 days. The influence of innervation on the expression of COX VIII and alpha-actin isoforms was examined in control, innervated, and denervated regenerating muscles at 3 and 10 days. The relative expression of COX VIII-L mRNA in denervated regenerating EDL muscles was significantly greater, while that of COX VIII-H was significantly less than in innervated regenerating EDL muscles after 10 days of regeneration. Similarly, cardiac alpha-actin mRNA levels were elevated in denervated regenerating EDL muscles after 10 days of regeneration. In conclusion, motor innervation influences the transition from the COX VIII-L to COX VIII-H isoform during myogenesis in regenerating muscles.

Actins↗
PubMed2000

Hyperinnervation during adrenal regeneration influences the rate of functional recovery.

The rat adrenal cortex has the uncommon ability to demonstrate morphological and functional regeneration after injury-induced loss of cortical tissue. Peripheral nerves are involved in tissue regeneration and healing after injury, implying that nerves may also be involved in modulating the regeneration of the adrenal cortex. Studies were initiated to assess changes in adrenal innervation during cortical tissue regeneration subsequent to adrenal enucleation. Innervation of regenerating adrenals was assessed from 3 to 62 days postenucleation by immunohistofluorescent detection of neuronal markers for primary afferent, preganglionic sympathetic, and postganglionic sympathetic fibers. The regenerating adrenal contained few nerves at 3 days postenucleation, but became differentially innervated, with extensive innervation by nerve fibers positive for calcitonin gene-related peptide (CGRP), tyrosine hydroxylase (TH), neuropeptide Y (NPY), and neuronal nitric oxide synthase (nNOS). In contrast, there was only minimal innervation by nerve fibers positive for vasoactive intestinal peptide. By 14 days postenucleation, the CGRP-, TH-, and NPY-positive innervation included areas of hyperinnervation in the capsule, cortex, and central inflammatory site of the regenerating gland. In addition, many chromaffin cells were present at all time points postenucleation. Quantification of the regenerating gland content of CGRP, norepinephrine, epinephrine, and nNOS verified the immunohistofluorescent observations. The period of extensive innervation correlated temporally with the time (3-30 days) during which the regenerating glands recovered steroidogenic function. Moreover, splanchnic nerve transection at the time of adrenal enucleation decreased the innervation by CGRP-positive and vesicular acetylcholine transporter-positive fibers and delayed regeneration. These results support the hypothesis that adrenal innervation modulates tissue regeneration and functional recovery of the enucleated adrenal gland.

Adrenal Medulla↗
PubMed2006

Gene expression analysis of zebrafish heart regeneration.

Mammalian hearts cannot regenerate. In contrast, zebrafish hearts regenerate even when up to 20% of the ventricle is amputated. The mechanism of zebrafish heart regeneration is not understood. To systematically characterize this process at the molecular level, we generated transcriptional profiles of zebrafish cardiac regeneration by microarray analyses. Distinct gene clusters were identified based on temporal expression patterns. Genes coding for wound response/inflammatory factors, secreted molecules, and matrix metalloproteinases are expressed in regenerating heart in sequential patterns. Comparisons of gene expression profiles between heart and fin regeneration revealed a set of regeneration core molecules as well as tissue-specific factors. The expression patterns of several secreted molecules around the wound suggest that they play important roles in heart regeneration. We found that both platelet-derived growth factor-a and -b (pdgf-a and pdgf-b) are upregulated in regenerating zebrafish hearts. PDGF-B homodimers induce DNA synthesis in adult zebrafish cardiomyocytes. In addition, we demonstrate that a chemical inhibitor of PDGF receptor decreases DNA synthesis of cardiomyocytes both in vitro and in vivo during regeneration. Our data indicate that zebrafish heart regeneration is associated with sequentially upregulated wound healing genes and growth factors and suggest that PDGF signaling is required.

Animals↗
PubMed2005

Chronic enhancement of the intrinsic growth capacity of sensory neurons combined with the degradation of inhibitory proteoglycans allows functional regeneration of sensory axons through the dorsal root entry zone in the mammalian spinal cord.

Peripherally conditioned sensory neurons have an increased capacity to regenerate their central processes. However, even conditioned axons struggle in the presence of a hostile CNS environment. We hypothesized that combining an aggressive conditioning strategy with modification of inhibitory reactive astroglial-associated extracellular matrix could enhance regeneration. We screened potential treatments using a model of the dorsal root entry zone (DREZ). In this assay, a gradient of inhibitory chondroitin sulfate proteoglycans (CSPGs) stimulates formation of dystrophic end bulbs on adult sensory axons, which mimics regeneration failure in vivo. Combining inflammation-induced preconditioning of dorsal root ganglia in vivo before harvest, with chondroitinase ABC (ChABC) digestion of proteoglycans in vitro allows for significant regeneration across a once potently inhibitory substrate. We then assessed regeneration through the DREZ after root crush in adult rats receiving the combination treatment, ChABC, or zymosan pretreatment alone or no treatment. Regeneration was never observed in untreated animals, and only minimal regeneration occurred in the ChABC- and zymosan-alone groups. However, remarkable regeneration was observed in a majority of animals that received the combination treatment. Regenerated fibers established functional synapses, as demonstrated electrophysiologically by the presence of an H-reflex. Two different postlesion treatment paradigms in which the timing of both zymosan and ChABC administration were varied after injury were ineffective in promoting regeneration. Therefore, zymosan pretreatment, but not posttreatment, of the sensory ganglia, combined with ChABC modification of CSPGs, resulted in robust and functional regeneration of sensory axons through the DREZ after root injury.

Animals↗
PubMed2006

Regeneration of vestibular otolith afferents after ototoxic damage.

Regeneration of receptor cells and subsequent functional recovery after damage in the auditory and vestibular systems of many vertebrates is well known. Spontaneous regeneration of mammalian hair cells does not occur. However, recent approaches provide hope for similar restoration of hearing and balance in humans after loss. Newly regenerated hair cells receive afferent terminal contacts, yet nothing is known about how reinnervation progresses or whether regenerated afferents finally develop normal termination fields. We hypothesized that neural regeneration in the vestibular otolith system would recapitulate the topographic phenotype of afferent innervation so characteristic of normal development. We used an ototoxic agent to produce complete vestibular receptor cell loss and epithelial denervation, and then quantitatively examined afferent regeneration at discrete periods up to 1 year in otolith maculas. Here, we report that bouton, dimorph, and calyx afferents all regenerate slowly at different time epochs, through a progressive temporal sequence. Furthermore, our data suggest that both the hair cells and their innervating afferents transdifferentiate from an early form into more advanced forms during regeneration. Finally, we show that regeneration remarkably recapitulates the topographic organization of afferent macular innervation, comparable with that developed through normative morphogenesis. However, we also show that regenerated terminal morphologies were significantly less complex than normal fibers. Whether these structural fiber changes lead to alterations in afferent responsiveness is unknown. If true, adaptive plasticity in the central neural processing of motion information would be necessitated, because it is known that many vestibular-related behaviors fully recover during regeneration.

Acoustic Maculae↗
PubMed1996

GH regulation of the Type 2 IGF receptor in regenerating skeletal muscle of rats.

GH enhances skeletal muscle growth, and IGF-II peptide is highly expressed during regeneration. We have therefore investigated the effect of GH administration on IGF-II binding and expression in regenerating rat skeletal muscle using the techniques of receptor autoradiography and in situ hybridisation. Notexin, a myotoxin, was injected into the right M. biceps femoris (day 0), causing affected fibres to undergo necrosis followed by rapid regeneration. Animals were administered either GH (200 micrograms/100 g body weight) or saline vehicle daily. Contralateral muscles were used as regeneration controls. GH administration during regeneration resulted in significant increases in body weight, and damaged and undamaged muscle weights (P < 0.001). IGF-II expression, which was examined in regenerating fibres, survivor fibres and undamaged fibres, varied according to tissue type (P < 0.001). Specifically, IGF-II expression in regenerating fibres was elevated relative to control and survivor fibres after day 3 (P < 0.05), with a peak on day 9 (P < 0.001). GH did not affect IGF-II message levels. 125I-IGF-II binding in regenerating muscle was examined in the same fibre types as well as in connective tissue. 125I-IGF-II binding in regenerating fibres was higher (P < 0.001) than in other tissue types on day 5. GH administration increased 125I-IGF-II binding in all damaged muscle tissues on day 5 (P < 0.001, regenerating fibres; P < 0.01, others). We believe that this shows for the first time an effect of GH on the Type 2 IGF receptor in regenerating skeletal muscle.

Animals↗
PubMed1995

Peripheral nerve injury and regeneration.

The process of nerve regeneration has been studied extensively by traditional morphological methods, but it is only recently that has been possible to identify more precisely the contribution of different nerve subpopulations. By studying different models of nerve repair and regeneration, it is becoming apparent that other tissue components are contributing to the overall process. When muscle grafting is carried out to repair an injured nerve, the regenerating axons are migrating in parallel with Schwann cells to bridge the nerve gap. The presence of Schwann cells is essential for a successful nerve regeneration, most probably because their production of different neuronal trophic factors. This pattern is also repeated when fibronectin mats are used for nerve repair, indicating the possibility to use this new synthetic matrix for clinical application. If the target organ is analysed after nerve repair, the recovery of all nerve components is evident. However, the process occurs at different times in separate skin compartments, and the regeneration of the autonomic innervation appears to be preceded by that of the sensory nerves. When looking at cutaneous nerve regeneration following different type of injury, a common pattern of events becomes apparent. In skin flaps, nerve regeneration begins from the skin surrounding the wound edge, or from the pedicle, and sensory nerves are the first to penetrate into the flap. Angiogenesis precedes reinnervation of the flap, and initially regenerating fibres appear to be associated with newly formed blood vessels. This pattern is evident also in full-thickness wounds and in suction blisters, where only the more superficial cutaneous layer is disrupted. Furthermore, the presence of keratinocytes appears to exert a directional influence on both regenerating blood vessels and nerves, which follow the regenerating keratinocytes when reepidermalisation is taking place. These results would indicate that there is a close relationship between nerve fibres and blood vessels during regeneration, with a substantial contribution to the process from other tissue components and soluble factors from the surrounding environment.

Animals↗
PubMed1994

[The refinement of retinotectal projection on tectal whole mount during the regeneration of the goldfish optic nerve labeled with DiI anterogradely].

The refinement of retinotectal projection during the regeneration of the goldfish optic nerve was studied with microinjection of the lipophilic dye DiI (1,1-dioctadecyl-3,-3,-3',-3',-tetramethylindo-carbocyanine perchlorate) into the dorsal retina to label a few of retinal ganglion cells, which could be transported anterogradely to their terminal arbors on the tectum. The regenerated optic nerve fibers on the tectal whole mount were examined at various time intervals (from 7 to 365 days) following an optic nerve crush. At the early regeneration stage (2 to 8 weeks postcrush), the regenerated optic fibers travelled in abnormal paths through both appropriate ventral and inappropriate dorsal hemitecta, but the majority of the fibers (about 60% to 70%) were found in the appropriate ventral hemitectum. At the late regeneration stage (2 months afterward postcrush), after refinement of regenerated optic fibers, the retinotectal projection was reestablished preciously as in the normal fish. Present study shows that the refinement of the retinotectal projection manifests in three major changes: 1) The disappearance of the regenerated optic fibers at the inappropriate tectal positions; 2) The disappearance of the side branches on the optic fiber shaft; 3) The formation of overlapping terminal arbors by the optic fibers that arrived at the retinotopic target. These results suggest that there may be two kinds of factors in the tectum: One is a common guiding factor which distributes over all the tectum and guides the regenerated optic fibers growing into the tectum at early regeneration; another is a position-specific neurotrophic factor which guides the regenerated optic fibers arriving at the retinotopic target at late regeneration.

Animals↗
PubMed1996

Regeneration of lower and upper jaws in urodeles is differentially affected by retinoic acid.

The vitamin A derivative retinoic acid (RA) is a powerful teratogen which can induce severe craniofacial and limb malformations if administered at certain stages of gestation. In addition this compound has been shown to affect patterning in regenerating systems. A classical example is the induction of supernumerary structures along the proximodistal axis of the regenerating amphibian limb. We have investigated the effect of RA on other regenerating systems, the amphibian lower and upper jaws, both in developing and adult animals. We report here that RA does not induce formation of extra structures either in the lower or in the upper jaw of adult newts under experimental conditions where duplications of the regenerating limb occur. However, RA selectively induces severe malformations in the upper jaw regenerate that resemble those induced in avian and mammalian embryos. Analysis of the expression of the newt retinoic acid receptors RAR alpha and delta in upper and lower jaws showed that RAR alpha was expressed at a significant level in the wound epidermis, but not in blastemal cells, whereas no RAR delta could be detected in the regenerate either by in situ hybridization or by using an anti-RAR delta antibody. Therefore, unlike in the limb, in jaws RAR delta is not up-regulated following amputation, and this difference in expression may be causally related to the different effects induced by RA on jaws and limbs. In order to establish whether retinoids affected regeneration of developing jaws in a similar fashion, their effects were studied in animals whose jaws had been amputated at different developmental stages. Under the experimental conditions used overall growth retardation and head defects were observed in the majority of embryos which had been amputated and treated with retinol palmitate (RP) between stages 26-28 and 38-39. In contrast, patterning of upper jaw regenerates in larvae amputated at stage 26-28 and 38-39. In contrast, patterning of upper jaw regenerates in larvae amputated at stage 45 was not significantly affected by the treatment, although the early phase of regeneration was slower than in controls. The different responses to retinoids of regenerating facial structures in embryos, larvae and adults will be discussed.

Abnormalities, Drug-Induced↗
PubMed2005

Regeneration of Nothofagus pumilio [Poepp. et Endl.] Krasser forests after five years of seed tree cutting.

Nothofagus pumilio [Poepp. et Endl.] Krasser is a deciduous tree species that grows in Chile and adjacent Argentina between 36 and 56 degrees S, often forming the Andean tree line. Silvicultural systems proposed for this species integrate both regeneration and intermediate level operations in an orderly process for managing forest stands. The seed-tree method of regeneration has been used to manage even-aged stands of this species. This paper investigates the effect of seed tree cuttings on the regeneration of Nothofagus pumilio [Poepp. et Endl.] Krasser forest located in the Magallanes region (Chile). The studied forest was managed on an even-aged basis using a seed tree silvicultural system for regeneration with an intensity of cutting of 65-70% of the basal area and a minimum of 15 dominant lenga trees per hectare retained. A regeneration inventory sampling was used to quantify regeneration attributes in the study area. Regeneration was found to be significantly affected by the seed tree cuttings. In fact, the number of established individuals rose from 0.39 to 26.7 plants m(-2) pre-harvest to 9.2-21.5 plants m(-2) post-harvest, depending on the particular development stage. Total regeneration ranged from 9.5 to 48.2 plants m(-2). The number of plants established over the period 1992-1997 was related to the residual basal area, coverage and number of trees. However, mean tree height was not significantly related to any regeneration variable. Significant variables were used to establish a regeneration prediction model using single and multiple linear equations (R2<0.418). Consequently, the seed tree method of regeneration can be considered feasible for commercially valuable lenga forests, although this method, in its strictest application, will create many large, irregularly shaped, even-aged groups.

Chile↗
PubMed1997

A randomized clinical trial of oxidized regenerated cellulose adhesion barrier (Interceed, TC7) alone or in combination with heparin.

OBJECTIVE: To compare the efficacy of heparin-saturated oxidized regenerated cellulose absorbable adhesion barrier, Interceed (TC7; Johnson and Johnson Medical Inc., New Brunswick, NJ) to oxidized regenerated cellulose alone for the prevention of postoperative adhesions. DESIGN: Clinical trial. By random assignment, one ovary was wrapped in oxidized regenerated cellulose, and the contralateral ovary was wrapped in oxidized regenerated cellulose saturated with a heparin solution (1,000 U/mL). PATIENT(S): Forty women with defects on both ovaries due to adhesiolysis and/or ovarian cystectomy. MAIN OUTCOME MEASURE: Adhesion formation and raw ovarian surface area were assessed at second-look laparoscopy 10 days to 16 weeks later. RESULT(S): At the second-look laparascopy-adhesions were present on 52.5% (21/40) of the ovaries treated with oxidized regenerated cellulose plus heparin and in 65% (26/40) of the contralateral ovaries treated with oxidized regenerated cellulose alone. For ovaries treated with oxidized regenerated cellulose plus heparin, the raw surface area was reduced from 9.41 +/- 1.27 cm2 (mean +/- SE) at laparotomy to 1.33 +/- 0.52 cm2 at second-look laparoscopy. The corresponding figures for ovaries treated with oxidized regenerated cellulose alone were from 10.24 +/- 1.08 to 1.92 +/- 0.54 cm2, respectively. The mean difference between the reductions in raw surface area (85.9% for oxidized regenerated cellulose plus heparin; 81.3% for oxidized regenerated cellulose alone) was not significantly different from zero (difference = - 0.24 cm2; 95% confidence interval = -2.56 to 3.04). CONCLUSION(S): Adding heparin did not enhance significantly the adhesion-reducing capacity of oxidized regenerated cellulose adhesion barrier when applied to ovarian surfaces after cystectomy and/or ovariolysis at laparotomy. This conclusion is subject to the possibility of a type II error.

Adult↗
PubMed2002

[Spatial heterogeneity and forest regeneration].

The research on spatial heterogeneity is meaningful for forest regeneration dynamics, which is a critical part in the forest ecosystem dynamics. Traditionally, forestry scientists are mainly concentrated their attention to the studies on the process of regeneration. However forests are spatiotemporal heterogeneous. In regeneration, there exists an ecological dynamic process at temporal scale, but also a heterogeneous pattern at spatial scale. Almost of the factors influencing forest regeneration, including both botic and abotic environment, both natural and human disturbances, and both characteristics of tree species and response of tree species to different disturbance agents, are spatially heterogeneous. Discussion on spatial heterogeneity and its effect on regeneration is indispensable for the understanding of the pattern, process and mechanism of forest regeneration. Main research contents and viewpoints of spatial heterogeneity in forest regeneration were summarised on the basis of available literature, and sources of spatial heterogeneity in the process of regeneration were analysed. The response of species to spatial heterogeneity, small-scale spatial heterogeneity and regeneration dynamics, spatial heterogeneity of lights in stand and regeneration pattern, and correlative relationships between the scales of soil heterogeneity and regeneration heterogeneity were reviewed.

Trees↗
PubMed1991

Regeneration of vitamin E in human platelets.

Human platelets possess active lipoxygenase and cyclooxygenase which convert arachidonic acid to (12S)-12-hydroperoxy-5,8,10,14-eicosatetraenoic acid (12-HPETE) plus (12S)-12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) and thromboxane B2 plus 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT), respectively. When platelet homogenates were incubated with arachidonate, there was a rapid consumption of platelet tocopherol. Time course analysis revealed that within 0.5 min, over half of arachidonate and tocopherol were metabolized. Mass formation of 12-HPETE and 12-HETE or thromboxane B2 and HHT exceeded that of the mass of tocopherol oxidized. Preincubation with the lipoxygenase inhibitor 5,8,11,14-eicosatetraynoic acid (ETYA) completely abolished this arachidonate-induced tocopherol oxidation whereas cyclooxygenase inhibitors (indomethacin and aspirin) further potentiated tocopherol oxidation, indicating that this oxidation is closely linked with platelet 12-lipoxygenase activity. Incubation with lipoxygenase metabolites of arachidonic acid showed that only 12-HPETE caused a rapid tocopherol oxidation which was followed by a gradual tocopherol regeneration. By using nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor which is also a strong reductant, over 60% of the arachidonate-induced oxidized tocopherol was regenerated. Tocopherol regeneration declined with increasing oxidation time induced by arachidonate, and after 30-60 min virtually no regeneration could be observed, suggesting that the precursor molecule was unstable. We postulate that the precursor molecule is the tocopheroxyl radical. In the presence of ETYA, a lipoxygenase inhibitor without antioxidant properties, either ascorbate or GSH provided significant tocopherol regeneration. Kinetic studies showed that tocopherol regeneration after the addition of ascorbate was essentially completed by 1 min. By contrast, GSH addition caused a steady increase in tocopherol which peaked after 10 min of its addition. To determine whether this rapid regeneration is chemical or enzymic, regeneration was studied in the presence of chloroform and methanol. Comparison of various reductants in this denaturing condition for enzymes showed that ascorbate and NDGA afforded significant regeneration whereas GSH was ineffective, indicating that there are distinct enzymic and non-enzymic mechanisms for tocopherol regeneration. This study provides direct evidence from mass analysis that tocopherol can be regenerated in human cell homogenates. This finding implies that maintenance of membrane tocopherol status may be an essential function of ascorbate and GSH which operate in concert to ensure maximum membrane protection against oxidative damage.

Arachidonate 12-Lipoxygenase↗
PubMed1994

Decreased rhodopsin regeneration in diabetic mouse eyes.

PURPOSE: To evaluate the effect of diabetes on rhodopsin regeneration in the excised mouse eye. METHODS: A superfused excised mouse eye preparation that exhibits rhodopsin regeneration after moderate bleaches and that is responsive to the composition of the perfusate was used. Diabetes was induced in albino mice (BALB/c) with the diabetogenic agent streptozotocin. Absorption spectrophotometry of the excised eye was used to monitor rhodopsin concentrations. RESULTS: Significant reductions in rhodopsin regeneration were observed in diabetic mice. Severely diabetic mice exhibited only 64% and 55% regeneration (at perfusate glucose levels of 5.1 mM and 10 mM, respectively), and moderately diabetic mice exhibited 74% and 73% regeneration, compared to the greater than 100% regeneration observed in nondiabetic mice. Glucose perfusate concentration has a major effect on rhodopsin regeneration. Lower concentrations of perfusate glucose (3 mM) reduced the amount of rhodopsin regeneration in both nondiabetic mice and diabetic mice. The diabetic mice seemed to tolerate higher concentrations of perfusate glucose (20 mM) better than the nondiabetic mice. Neither correction for osmolarity nor substitution with a nonglycolytic substrate increased the amount of rhodopsin regeneration in the diabetic mice. CONCLUSIONS: Diabetes reduced the amount of rhodopsin regeneration that followed moderate bleaches in excised mouse eyes. The data suggest that some process or processes associated with rhodopsin regeneration have been affected in the diabetic.

Animals↗
PubMed2005

Matrix inclusion within synthetic hydrogel guidance channels improves specific supraspinal and local axonal regeneration after complete spinal cord transection.

We have previously shown that a novel synthetic hydrogel channel composed of poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) (pHEMA-MMA) is biocompatible and supports axonal regeneration after spinal cord injury. Our goal was to improve the number and type of regenerated axons within the spinal cord through the addition of different matrices and growth factors incorporated within the lumen of the channel. After complete spinal cord transection at T8, pHEMA-MMA channels, having an elastic modulus of 263+/-13 kPa were implanted into adult Sprague Dawley rats. The channels were then filled with one of the following matrices: collagen, fibrin, Matrigel, methylcellulose, or smaller pHEMA-MMA tubes placed within a larger pHEMA-MMA channel (called tubes within channels, TWC). We also supplemented selected matrices (collagen and fibrin) with neurotrophic factors, fibroblast growth factor-1 (FGF-1) and neurotrophin-3 (NT-3). After channel implantation, fibrin glue was applied to the cord-channel interface, and a duraplasty was performed with an expanded polytetrafluoroethylene (ePTFE) membrane. Controls included animals that had either complete spinal cord transection and implantation of unfilled pHEMA-MMA channels or complete spinal cord transection. Regeneration was assessed by retrograde axonal tracing with Fluoro-Gold, and immunohistochemistry with NF-200 (for total axon counts) and calcitonin gene related peptide (CGRP, for sensory axon counts) after 8 weeks survival. Fibrin, Matrigel, methylcellulose, collagen with FGF-1, collagen with NT-3, fibrin with FGF-1, and fibrin with NT-3 increased the total axon density within the channel (ANOVA, p<0.05) compared to unfilled channel controls. Only fibrin with FGF-1 decreased the sensory axon density compared to unfilled channel controls (ANOVA, p<0.05). Fibrin promoted the greatest axonal regeneration from reticular neurons, and methylcellulose promoted the greatest regeneration from vestibular and red nucleus neurons. With Matrigel, there was no axonal regeneration from brainstem motor neurons. The addition of FGF-1 increased the axonal regeneration of vestibular neurons, and the addition of NT-3 decreased the total number of axons regenerating from brainstem neurons. The fibrin and TWC showed a consistent improvement in locomotor function at both 7 and 8 weeks. Thus, the present study shows that the presence and type of matrix contained within synthetic hydrogel guidance channels affects the quantity and origin of axons that regenerate after complete spinal cord transection, and can improve functional recovery. Determining the optimum matrices and growth factors for insertion into these guidance channels will improve regeneration of the injured spinal cord.

Animals↗
PubMed2004

Reconstruction of ablated rat rectus abdominis by muscle regeneration.

Skeletal muscle regeneration is a powerful, naturally occurring process of tissue reconstruction that follows myofiber damage secondary to myotoxic injury that does not normally affect the tissue circulation and scaffold. The ablated tissue, in traumatology and free muscle grafts, is frequently replaced by scars. The final outcome is poor even after in situ myoblast seeding of the harvested muscle. The goal of this study was to identify protocols to reconstruct muscle tissue, even in such adverse environments. The authors applied a step-by-step approach to identify factors favoring the survival of autologous satellite cells and, thus, muscle regeneration. In a rat model of full-thickness rectus abdominis muscle ablation, autologous myoblasts were isolated from the explanted rectus abdominis and seeded in a homologous acellular matrix immediately after wall reconstruction (group 1, five animals). In group 2 (five animals), the ablated rectus abdominis was autografted in situ. In a third group of five rats, Marcaine was injected into both the autograft and the surrounding abdominal wall muscle. Three weeks after surgery, serial cross-sections of the reconstructed abdominal wall were stained with hematoxylin and eosin or embryonic myosin antibody, a well-characterized molecular marker of early myogenesis in development and regeneration. Percentages of the patch area covered by regenerated myofibers were determined by morphometry. When autologous myoblasts were seeded in a homologous acellular matrix, the only myofibers observed to regenerate were those along the border of the patch. Autografting of the middle third of the rectus abdominis muscle similarly resulted in scar formation. The few muscle cells in the graft core were scanty myoblasts that could be detected only by monoclonal embryonic myosin antibody. Although negative for myofiber regeneration, the results in both cases confirmed the mechanical patency of the patches with regard to abdominal organ support. Myofibers were successfully regenerated in the graft by injecting Marcaine into both the autograft and the surrounding muscles. Three weeks after surgery, the patch was paved with young, centrally nucleated myofibers intermixed with young myofibers and myotubes expressing embryonic myosin. The difference in percentage of patch area covered by regenerated myofibers in group 3 (Marcaine injection around the patch, 81.6 +/- 3.0 percent) (mean +/- SD) versus either group 1 (Myoblast-seeded acellular patch, 18.0 +/- 3.0 percent) or group 2 (Autograft, 25.8 +/- 7.0 percent) was statistically significant on independent t test analysis (p < 0.0001). Even an acellular matrix showed some myofiber regeneration after surrounding muscles had been injected with Marcaine. This is the first successful evidence of muscle reconstruction after full-thickness ablation of the middle third of the rectus abdominis. Muscle regeneration seems to be the result of successive waves of migration of angioblasts and then satellite cell-derived myoblasts from the muscles surrounding the patch. The results strongly suggest that vascularization of the scaffold and successive coordinate proliferation of the seeded cells are required for myoblasts to be able to migrate into the patch and differentiate up to myofiber stage.

Animals↗
PubMed2000

Role of retinoic acid in lens regeneration.

Prompted by the actions of retinoids and their receptors in gene regulation, in the developing eye and especially in the lens, we have undertaken a detailed study to examine the effects of retinoids on urodele lens regeneration. First, we examined the effects of exogenous retinoids. It was found that exogenous retinoids had no significant effect on lens regeneration. However, when synthesis of retinoic acid was inhibited by disulfiram, or when the function of the retinoid receptors was impaired by using a RAR antagonist, the process of lens regeneration was dramatically affected. In the majority of the cases, lens regeneration was inhibited and lens morphogenesis was disrupted. In a few cases, we were also able to observe ectopic lens regeneration from places other than the normal site, which is from the dorsal iris. The most spectacular case was the regeneration of a lens from the cornea, an event possible only in premetamorphic frogs. These data show that inhibition of retinoid receptors is paramount for the normal course and distribution of lens regeneration. We have also examined expression of RAR-delta during lens regeneration. This receptor was expressed highly in the regenerating lens only. Therefore, it seems that this receptor is specific for the regeneration process and consequently such expression correlates well with the effects of RAR inhibition observed in our studies.

Animals↗
PubMed1989

Prevention of optic nerve regeneration in the frog Hyla moorei transiently delays the death of some ganglion cells.

We have previously reported that a proportion of ganglion cells die during optic nerve regeneration in the adult frog Hyla moorei (Humphrey and Beazley, '85). Here we assess the effect of preventing optic nerve regeneration on this cell loss. The optic nerve was crushed unilaterally and regeneration was allowed to progress unimpeded in one experimental series but was prevented by ligating or capping the nerve in another. We estimated total cell numbers in the ganglion cell layer from cresyl-stained wholemounts, comparing each experimental retina with its unoperated partner. At 70-78 days postcrush, mean cell numbers had fallen by 31.5% for frogs with unimpeded regeneration (N = 9), a significantly greater reduction than the 21.5% (N = 8) loss for the impeded regeneration series (p less than 0.001). Thereafter, cell numbers were stable for frogs with unimpeded regeneration. Cell death continued in the series with impeded regeneration, and losses exceeded those of frogs with unimpeded regeneration from 110 days postcrush. When regeneration was impeded, ganglion cell somas underwent an intense cell soma reaction and became arranged in rows radiating from the optic nerve head. Our findings indicate that some ganglion cells are transiently spared when regeneration of their axons is prevented. The abnormally extensive contacts formed between somas may delay ganglion cell loss. However, the eventual death of most ganglion cells shows them to be target-independent in the long term.

Animals↗