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PubMed2001

Effects of locomotor training on hindlimb regeneration in the urodele amphibian Pleurodeles waltlii.

1. The effects of locomotor training on hindlimb regeneration were studied in the urodele amphibian Pleurodeles waltlii. 2. After amputation of one hindlimb at mid-femur, adult animals were subjected to regular training sessions (1 h daily, 5 days a week, over 8 months) of terrestrial stepping. 3. Eight months post-amputation, trained animals exhibited regenerated limbs of reduced size as compared to animals kept in their aquaria. Histological data showed an abnormal regeneration of both the femur and distal structures (e.g. digit muscles, metatarsi and phalanges) while medial structures (e.g. tibia and fibula) were totally re-formed. The study of the electromyographical activity in regenerated limbs during stepping and that of their reflex responsiveness to electrical stimulation showed that both motor and sensory innervations were functional in the limb stump of trained animals. 4. The regenerative capacity of the abnormal stumps was preserved since following a second amputation a quite normal hindlimb was regenerated in 3 months, provided the re-amputated animals were not trained to terrestrial stepping. 5. The stress due to handling, change in locomotor medium (aquatic vs. terrestrial) and the friction of the wound epidermis with the ground were not involved in the disruption of limb regeneration. 6. The locomotor pattern, the reflex responsiveness and the muscle fibre composition were similar in supernumerary forelimbs grafted on the back and in normal forelimbs. However, the supernumerary forelimbs regenerated normally even in animals subjected to locomotor training while the hindlimb did not. It is concluded that the disrupting effects of locomotor training on limb regeneration were localized to the the limb directly involved in locomotion. 7. The mechanisms underlying abnormal limb regeneration in animals subjected to locomotor training are discussed.

Animals↗
PubMed1983

Accurate regeneration of an electrical synapse between two leech neurones after destruction of the ensheathing glial cell.

An interneurone, the S cell in the central nervous system of the leech, regenerates its severed axon and forms an electrical synapse with its target, another S cell, entirely within the ensheathment of two glial cells. After the two glial cells were killed selectively by intracellular injection of protease, axonal regeneration and synapse formation occurred in a normal fashion during the month following nerve injury. Soon after reconnexion of S cells, the conduction of impulses across the non-rectifying electrical junction between the cells was more reliable from the target than into it from the thinner regenerating axon. The distal segments of severed S-cell axons survived for weeks or months after destruction of their glial cells, indicating that the ensheathing glia is not required for long-term survival of axon segments. The distal axon segment of the S cell remained connected to the target axon at the normal region of synapse midway between ganglia within the nerve cord. In about half the cases in which reconnexion between injured S cell and target S cell occurred between 10 and 25 days following nerve crush, the regenerating neurone had formed an electrical synapse with its severed distal axon and had thereby become reconnected, indirectly, with its target. In the other cases, reconnexion was by direct contact. By 4 weeks, the proportion of injured S cells that were coupled and making direct contact with their targets rose to more than 80% of the total population, indicating that regeneration continued until the two S cells contacted one another directly. This is similar to the course of S-cell regeneration in the presence of the ensheathing glia. Microscopy of the regenerating neurone and both its distal axon segment and its target showed that the site of synapse formation in the absence of the usual glial sheath was normal. Fluorescence microscopy following intracellular injection of Lucifer Yellow dye, which crosses between S cells at the electrical synapse, showed that the regenerated synapse formed specifically between S cells. Moreover, the target did not form alternative synapses when regeneration failed.

Animals↗
PubMed2003

Cells derived from regenerated endothelium of the porcine coronary artery contain more oxidized forms of apolipoprotein-B-100 without a modification in the uptake of oxidized LDL.

Increased accumulation of lipoproteins and cholesterol within cells from regenerated endothelium may be responsible for their reported dysfunction. This study compared the presence and uptake of oxidized forms of low-density lipoprotein (LDL) in cells derived from native and regenerated endothelium. Four weeks after balloon denudation, primary cultures of native and regenerated endothelial cells were prepared from porcine coronary arteries. Regenerated endothelium stained more strongly using an antibody against oxidized lipoproteins. The increase in oxidized forms of apolipoprotein-B-100 exhibited by cells from regenerated endothelium was not due to an increase in extracellular-induced oxidation of native LDL, measured as the production of thiobarbituric-acid-reactive substances, being identical in both cell types. Intracellular cholesterol and cholesterol ester content were unchanged in regenerated cells. Using flow cytometry, accumulation of oxidized LDL was investigated further by quantifying the uptake of a mildly oxidized preparation of 1,1'-dioctadecyl-3,3,3',3-tetramethyl-indocarbocyanine perchlorate-labelled LDL. The parameters of uptake, EC(50) and E(max), were not different between cells from native and regenerated endothelium suggesting that the number of LOX-1 receptors was identical in the two cell types. Moreover, a negative correlation between the increased uptake of acetylated LDL and decreased cGMP production in response to bradykinin was observed in cells from regenerated endothelium. Thus, the increased incorporation of modified LDL and their intracellular oxidation could be responsible for the alteration in NO production. The presence of oxidized forms of LDL may be a marker of endothelium regeneration and could be involved in the endothelial dysfunction of pig coronary arteries 4 weeks after balloon denudation.

Animals↗
PubMed1995

Comparison of rabbit facial nerve regeneration in nerve growth factor-containing silicone tubes to that in autologous neural grafts.

Previous reports suggest that nerve growth factor (NGF) enhanced nerve regeneration in rabbit facial nerves. We compared rabbit facial nerve regeneration in 10-mm silicone tubes prefilled with NGF or cytochrome C (Cyt C), bridging an 8-mm nerve gap, to regeneration of 8-mm autologous nerve grafts. Three weeks following implantation, NGF-treated regenerates exhibited a more mature fascicular organization and more extensive neovascularization than Cyt C-treated controls. Morphometric analysis at the middle of the tube of 3- and 5-week regenerates revealed no significant difference in the mean number of myelinated or unmyelinated axons between NGF- and Cyt C-treated implants. However, when the numbers of myelinated fibers in 5-week regenerates were compared to those in their respective preoperative controls, NGF-treated regenerates had recovered a significantly greater percentage of myelinated axons than Cyt C-treated implants (46% versus 18%, respectively). The number of regenerating myelinated axons in the autologous nerve grafts at 5 weeks was significantly greater than the number of myelinated axons in the silicone tubes. However, in the nerve grafts the majority of the axons were found in the extrafascicular connective tissue (66%). The majority of these myelinated fibers did not find their way into the distal nerve stump. Thus, although the number of regenerating myelinated axons within the nerve grafts is greater than that of axons within silicone tube implants, functional recovery of autologous nerve graft repairs may not be superior to that of intubational repairs.

Animals↗
PubMed2006

Metallothionein and liver cell regeneration.

Hepatocytes in adults are in a nonproliferative state but they have high capacity to regenerate within few hours after an injury. After partial hepatectomy or chemical injury, hepatocytes undergo a synchronized multistep process consisting of priming/initiation, proliferation, and termination. These distinct steps are essential for restoring the structure and functions of liver. The mechanisms involved in each of these steps of regeneration are well documented from various laboratories and are described in several reviews. We briefly describe these steps and the involvement of various cytokines and growth factors for cell regeneration in this short review. Liver cell regeneration may also involve stem cell proliferation. The regenerating cells require large amounts of zinc within a short time, and this requirement is met by induction of a zinc and copper binding protein, metallothionein (MT), during the priming step, soon after an injury. There are several reports on the transfer of zinc from MT to various metalloenzymes and transcription factors. Genetically modified mouse models have been used to study the involvement of interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha in cell regeneration. The use of an MT-knockout mouse has enabled us to investigate the specific role of MT in liver regeneration after partial hepatectomy, chemical injury, and fibrosis. Several studies have suggested a defective liver regeneration after an injury in MT-knockout mice. There is cumulative evidence that indicates an essential role for MT in liver cell regeneration.

Animals↗
PubMed1993

Gene expression during imaginal disc regeneration detected using enhancer-sensitive P-elements.

When imaginal disc fragments from Drosophila are cultured in adult female hosts, they either duplicate the part of the pattern specified by the fate map, or regenerate to replace the missing part. The new tissue is added by proliferation of a small number of cells from the cut edge, brought together when the wound heals to form a regeneration blastema. Specification of the new pattern has been explained by assuming interactions among cells of different positional value in the regeneration blastema. In order to identify genes which might mediate these events, we screened over eight hundred independently isolated autosomal insertions of an enhancer-sensitive P-element, for altered lac-z expression in regenerating discs following cell death induced by a temperature-sensitive cell-lethal mutation. Two further screens divided the positive lines into four groups based on appropriate timing of the lac-z response in the cell-lethal mutant background and the expected response to an alternate source of cell death. Expression in wing disc fragments cultured in vivo was most frequent in the target class defined by the screens. In this direct test, lac-z expression was found in 23 lines and in most cases was spatially and temporally correlated with the formation of the regeneration blastema. Our results suggest a very substantial transcriptional response during the early stages of imaginal disc regeneration. lac-z expression in control imaginal discs, embryos and adult ovaries of the positive lines was also assayed. The selected insertions included: a small class expressed only in discs undergoing regeneration and apparently not at any other stage, possibly representing genes active exclusively in regeneration; a larger class expressed in the embryo or during oogenesis, but not normally in imaginal discs, as expected for functions recruited from earlier stages of the developmental program; and finally a class with spatially patterned expression in normal discs. This class included several insertions with expression associated with compartment boundaries, including one at the decapentaplegic (dpp), and one at the crumbs (crb) locus, a growth factor homologue, and an EGF-repeat gene respectively. Some of the expression patterns observed in cultured disc fragments provide evidence for cell communication in the regeneration blastema.

Animals↗
PubMed1994

A zebrafish retinoic acid receptor expressed in the regenerating caudal fin.

Retinoic acid (RA) is an important signalling molecule in vertebrate pattern formation both in developing and regenerating tissues. The effects of RA are due largely to regulation of gene transcription, mediated by retinoic acid receptors (RAR-alpha, RAR-beta, RAR-gamma) and retinoid X receptors (RXR-alpha, RXR-beta, RXR-gamma). We have been using zebrafish as a model of regeneration to study the role of retinoic acid and its receptors in vertebrate pattern formation. In this report, we describe the molecular cloning and characterization of one of the zebrafish RARs that is the predominant receptor in the regenerating caudal fin and corresponds most closely to the RAR-gamma subtype isolated from mouse and human and to RAR-delta from newt. Zebrafish RAR-gamma (zfRAR-gamma) exhibits both structural and functional conservation with its mammalian counterparts. Studies utilizing both normal and regenerating caudal fins of the zebrafish have indicated that it is the RAR-gamma subtype, compared to RAR-alpha or RAR-beta, which is expressed at the highest levels in the tail fin. To localize the expression pattern of RAR-gamma during fin regeneration, we have carried out whole-mount in situ hybridization. ZfRAR-gamma transcripts, during fin regeneration, are localized in the blastemal tissue formed at the distal ends of the bony rays following amputation. Treatment of fish with RA during fin regeneration induces a number of striking morphological effects on the regenerate. When amputations are performed distal to the branch points or dichotomies, where a single ray bifurcates to extend two individual 'daughter' rays, RA treatment causes a dichotomy reduction where the two 'daughter' rays fuse to once again form a single ray. The single ray subsequently bifurcates in a comparatively normal manner. Our data suggest that exogenous RA can respecify pattern in the regenerating caudal fin and identifies the blastemae as possible RA target tissues.

Animals↗
PubMed1994

Selective regeneration of photoreceptors in goldfish retina.

Previous work has shown that the neural retina in adult goldfish can regenerate. Following retinal damage elicited by surgical or cytotoxic lesions, missing neurons are replaced by foci of proliferating neuroepithelial cells, which previous studies have suggested are derived from rod precursors. In the intact retina, rod precursors proliferate but produce only new rods. The regenerative responses observed previously have involved replacement of neurons in all retinal layers; selective regeneration of specific neuronal types (except for rod photoreceptors) has not been reported. In the experiments described here, we specifically destroyed either cones alone or cones and rods with an argon laser, and we found that both types of photoreceptors regenerated within a few weeks. The amount of cone regeneration varied in proportion to the degree of rod loss. This is the first demonstration of selective regeneration of a specific class of neuron (i.e., cones) in a region of central nervous tissue where developmental production of that class of neuron has ceased. Selective regeneration may be limited to photoreceptors, however, because when dopaminergic neurons in the inner retina were ablated with intraocular injections of 6-hydroxydopamine, in combination with laser lesions that destroyed photoreceptors, the dopaminergic neurons did not regenerate, but the photoreceptors did. These data support previous studies which showed that substantial cell loss is required to trigger regeneration of inner retinal neurons, including dopaminergic neurons. New observations here bring into question the presumption that rod precursors are the only source of neuronal progenitors during the regenerative response. Finally, a model is presented which suggests a possible mechanism for regulating the phenotypic fate of retinal progenitor cells during retinal regeneration.

Animals↗
PubMed1997

Planarian Hox genes: novel patterns of expression during regeneration.

Platyhelminthes are widely considered to be the sister group of coelomates (Philippe, H., Chenuil, A. and Adoutte, A. (1994)Development 1994 Supplement, 15-24) and the first organisms to show bilateral symmetry and cephalization. Within this phylum, the freshwater planarians (Turbellaria, Tricladida) have been used as model systems for studying bidirectional regeneration (Slack, J. M. W. (1980) J. Theor. Biol 82, 105-140). We have been attempting to identify potential pattern-control genes involved in the regeneration of planarian heads and tails after amputation. Since Hox cluster genes determine positional identity along the anteroposterior axis in a wide range of animals (Slack, J. M. W., Holland, P. W. H. and Graham, C. F. (1993) Nature 361,490-492), we performed an extensive search for Hox-related genes in the planarian Dugesia(G)tigrina. Sequence analyses of seven planarian Dthox genes (Dthox-A to Dthox-G) reveal high similarities with the homeodomain region of the Hox cluster genes, allowing us to assign planarian Dthox genes to anterior and medial Hox cluster paralogous groups. Whole-mount in situ hybridization studies in regenerating adults showed very early, synchronous and colocalized activation of Dthox-D, Dthox-A, Dthox-C, Dthox-E, Dthox-G and Dthox-F. After one hour of regeneration a clear expression was observed in all Dthox genes studied. In addition, all seemed to be expressed in the same regenerative tissue, although in the last stages of regeneration (9 to 15 days) a differential timing of deactivation was observed. The same Dthox genes were also expressed synchronously and were colocalized during intercalary regeneration, although their expression was delayed. Terminal regeneration showed identical Dthox gene expression in anterior and posterior blastemas, which may prevent these genes from directing the distinction between head and tail. Finally, continuous expression along the whole lateral blastema in sagittal regenerates reflected a ubiquitous Dthox response in all types of regeneration that was not related specifically with the anteroposterior polarity.

Amino Acid Sequence↗
PubMed2006

Growth or differentiation? Adaptive regeneration in the brittlestar Amphiura filiformis.

Amphiura filiformis is a burrowing brittlestar, which extends arms in the water column when suspension feeding. In previous studies, unexpectedly high variability was observed in regeneration rate between individuals even when experiments were performed under identical conditions. The aims of this work were to understand this variability and interpret the observed variability in terms of adaptation to sublethal predation. Our experiments on the dynamics of arm regeneration in A. filiformis revealed that the developmental program during regeneration is well adapted to its burrowing life style. We demonstrate that there is a trade-off between regeneration in length and functional recovery for feeding (differentiation index). The amount of tissue lost (length lost), which represents the quantity of tissue needed to completely regenerate an intact arm with no previous history of regeneration, determines whether the arm will invest more energy in growth and/or in differentiation, which must be a reflection of the ability to differentially regulate developmental programs during regeneration. We show that combining regeneration rate with differentiation index provides an ideal tool for the definition of a standard temporal framework for both field and laboratory studies of regeneration.

Adaptation, Physiological↗
PubMed2003

Regeneration therapy for diabetes mellitus.

Regeneration therapy can be classified into three categories. The first category, in vitro regeneration therapy, makes use of transplanted cultured cells, including embryonic stem (ES) cells, pancreatic precursor cells and beta-cell lines, in conjunction with immunosuppressive therapy or immunoisolation for the treatment of patients with Type 1 diabetes. In the second type of regeneration therapy, ex vivo regeneration therapy, a patient's own cells, such as bone marrow stem cells, are transiently removed and induced to differentiate into beta-cells in vitro. However, at the present time, insulin-producing cells cannot be generated from bone marrow stem cells. In vivo regeneration therapy, the third type of regeneration therapy, enables impaired tissue to regenerate from a patient's own cells in vivo. beta-Cell neogenesis from non-beta-cells, and beta-cell proliferation in vivo have been considered in particular as regeneration therapies for patients with Type 2 diabetes. Regeneration therapy for pancreatic beta-cells can be combined with various other therapeutic strategies, including islet transplantation, cell-based therapy, gene therapy and drug therapy, to promote beta-cell proliferation and neogenesis; it is hoped that these strategies will, in the future, provide a cure for diabetes.

Animals↗
PubMed1993

Roles of embryonic astrocytes and Schwann cells in regeneration of adult rat dorsal root axons: qualitative observations.

Transplants of fetal spinal cord support regeneration of severed dorsal root axons and allow synapse formation. To analyze the components of the transplants that provide this favorable environment, we studied whether or not 1) the embryonic spinal cord transplants contain Schwann cells, a major producer of laminin, and 2) whether dorsal roots regenerate into transplants of immature astrocytes. We used calcitonin gene-related peptide (CGRP), laminin and glial fibrillary acidic protein (GFAP) immunocytochemistry to identify regenerated axons, Schwann cells and astrocytes, respectively. CGRP-immunoreactive axons regenerated into embryonic day 14 fetal spinal cord transplants, but the transplant did not contain laminin. Dorsal roots immunoreactive for CGRP also regenerated into suspensions of cultured astrocytes. The transplanted astrocytes also favored the expression of laminin and GFAP. CGRP-labeled axons regenerated and distributed widely into the polycarbonate tubes coated with poly L-lysine and containing medium with or without cultured astrocytes. These results indicate that Schwann cells are not likely to account for dorsal root regeneration into transplants of fetal spinal cord and that astrocytes may in fact induce regeneration. Regeneration may also take place in response to various environments.

Animals↗
PubMed1977

Limb regeneration in fiddler crabs: species differences and effects of methylmercury.

1. When kept under identical conditions, Uca pugnax regenerates limbs and molts more rapidly than U. pugilator from the same location. 2. The tropical species U. rapax and U. speciosa also regenerate faster than U. pugilator from the same location. U. thayeri is the slowest to replace missing limbs, the slowest to harden the carapace after ecdysis, and also requires the greatest injury before autotomy will take place. 3. When kept in groups, U. thayeri stops regeneration after basal growth and will not molt; U. pugilator is only slightly retarded when kept in groups. U. rapax is also affected by grouping, showing a lengthened proecdysial phase and terminal plateau, thus also delaying molting. 4. Newly regenerated limbs of U. rapax, U. thayeri, and U. speciosa, aside from being lighter than old limbs, have a conspicuous banding pattern. This pattern becomes less obvious during the week or two after ecdysis as melanophores move into the interband regions and the limb as a whole darkens due to increased dispersion of pigment in the melanophores. In U. pugilator the newly regenerated limbs are very pale in color and remain that way for several months under laboratory conditions, even when animals are maintained on a dark background. 5. When treated with 0.5 mg/liter methylmercury, growth was inhibited entirely in U. thayeri. Partial inhibition was seen in U. pugilator, and the least inhibition in U. rapax. A few individuals of U. rapax were able to complete regeneration and molt, but there was no melanin in the regenerated limbs. 6. Inhibition of melanogenesis in regenerated limbs was also seen in U. thayeri and to a smaller extent in U. pugilator at 0.1 mg/liter methylmercury. The lack of black pigment may be due to an inhibition of cell migration but more likely of melanin synthesis. Some of these crabs developed melanin when kept in clean water after ecdysis. 7. Seasonal differences were noted in all species, but especially in U. Thayeri. In this species, regenerated occurred much more rapidly in March-April than in January.

Animals↗
PubMed2000

Maintaining the line of defense: regeneration of Cuvierian tubules in the sea cucumber Holothuria forskali (Echinodermata, Holothuroidea).

When irritated, individuals of the sea cucumber Holothuria forskali expel a few Cuvierian tubules which lengthen, instantly become sticky, and rapidly immobilize most organisms with which they come into contact. After expulsion, the lost tubules are readily regenerated. When only a few tubules have been expelled, there is often a latent period before the regeneration starts. In contrast, when many tubules have been expelled, the regenerative process starts immediately but proceeds in successive waves of 10 to 30 tubules that begin to regenerate at 10-day intervals. However, in all cases, the complete regeneration of a given tubule takes about 5 weeks and may be divided into three successive phases: an initial repair phase including the overall 48-h post-autotomy period, a true regenerative phase taking about 4 weeks to complete, and a growth phase of about one more week. Initial regeneration events occur by epimorphosis, cell proliferation being essential to the regenerative process, whereas late events occur mainly by morphallaxis, with migration of the newly differentiated cells. The mesothelium is the tissue layer in which cell proliferation is the most precocious and the most important, involving both peritoneocytes and undifferentiated cells (which seem to be dedifferentiated peritoneocytes). As regeneration proceeds, the percentage of undifferentiated cells regularly decreases in parallel with the differentiation of granular (adhesive-secreting) cells and myocytes. The myocytes then separate off from the mesothelium and migrate within the connective tissue layer. Three types of pseudopodial cells follow one another in the tubule connective tissue during regeneration. Type 1 cells have all the characteristics of echinoderm phagocytes and may have a fibroblastic function, cleaning the connective tissue compartment before new collagen synthesis starts. Type 2 cells are rather undifferentiated and divide actively. The presence of type 3 cells is closely associated with the appearance of collagen fibers, and it is suggested that they have a fibroblastic function. In the inner epithelium, cells also divide actively, but only those in which spherules have not yet differentiated in the basal intraconnective processes. It appears, therefore, that in the three tissue layers of the tubules, regeneration proceeds by cell dedifferentiation, then proliferation, and finally by differentiation. Cuvierian tubules thus constitute a very efficient defensive mechanism: their large number, sparing use, and particular regeneration dynamics make them an almost inexhaustible line of defense maintained at limited energy cost.

Animals↗
PubMed2000

Bone regeneration at rabbit skull defects treated with transforming growth factor-beta1 incorporated into hydrogels with different levels of biodegradability.

OBJECT: Skull bone regeneration induced by transforming growth factor-beta1 (TGFbeta1)-containing gelatin hydrogels (TGFbeta1-hydrogels) was investigated using a rabbit skull defect model. Different strengths of TGFbeta1 were examined and compared: different TGFbeta1 doses in gelatin hydrogels with a fixed water content, different water contents in gelatin hydrogels with a fixed TGFbeta1 dose, and TGFbeta1 in solution form. In addition, regenerated skull bone was observed over long time periods after treatment. METHODS: Soft x-ray, dual energy x-ray absorptometry, and histological studies were performed to assess the time course of bone regeneration at a 6-mm-diameter skull defect in rabbits after treatment with TGFbeta1-hydrogels or other agents. The influence of TGFbeta1 dose and hydrogel water content on skull bone regeneration by TGFbeta1-hydrogels was evaluated. Gelatin hydrogels with a water content of 95 wt% that incorporated at least 0.1 microg of TGFbeta1 induced significant bone regeneration at the rabbit skull defect site 6 weeks after treatment, whereas TGFbeta1 in solution form was ineffective, regardless of dose. The in vivo degradability of the hydrogels, which varied according to water content, played an important role in skull bone regeneration induced by TGFbeta1 -hydrogels. In our hydrogel system, TGFbeta1 is released from hydrogels as a result of hydrogel degradation. When the hydrogel degrades too quickly, it does not retain TGFbeta1 or prevent ingrowth of soft tissues at the skull defect site and does not induce bone regeneration at the skull defect. It is likely that hydrogel that degrades too slowly physically impedes formation of new bone at the skull defect. Following treatment with 0.1-microg TGFbeta1-hydrogel (95 wt%), newly formed bone remained at the defect site without being resorbed 6 and 12 months later. The histological structure of the newly formed bone was similar to that of normal skull bone. Overgrowth of regenerated bone and tissue reaction were not observed after treatment with TGFbeta1 -hydrogels. CONCLUSIONS: A TGFbeta1-hydrogel with appropriate biodegradability will function not only as a release matrix for the TGFbeta1, but also as a space provider for bone regeneration. The TGFbeta1-hydrogel is a promising surgical tool for skull defect repair and skull base reconstruction.

Absorptiometry, Photon↗
PubMed2003

Rapid hepatocyte nuclear translocation of the Forkhead Box M1B (FoxM1B) transcription factor caused a transient increase in size of regenerating transgenic hepatocytes.

The Forkhead Box (Fox) proteins are an extensive family of transcription factors that shares homology in the winged helix DNA binding domain. Liver regeneration studies with the -3 kb transthyretin (TTR) promoter-driven FoxM1B transgenic (TG) mice demonstrated that premature hepatocyte nuclear localization of the FoxM1B transgene protein at 16 h following partial hepatectomy (PHx) caused an 8-h acceleration in the onset of hepatocyte DNA replication (S-phase) and mitosis by stimulating earlier expression of cell cycle genes. Whether the FoxM1B transgene protein participates in immediate early events during liver regeneration remains to be determined. Here, we found that the FoxM1B transgene protein translocated to hepatocyte nuclei immediately following PHx, that its nuclear staining persisted for the first 6 h after surgery, and that this translocation was associated with an increase in size of regenerating TG hepatocytes. However, regenerating TTR-FoxM1B liver did not exhibit altered expression of proteins that have been implicated in mediating increased cell size, including serum-and-gucocorticoid-inducible protein kinase (SGK), protein kinase-B/Akt, the tumor suppresser gene PTEN (negative regulator of the PI3K/Akt pathway), c-Myc, or peroxisome proliferation. Moreover, we demonstrated that hepatocyte nuclear translocation of the FoxM1B transgene protein was rapidly induced during the hepatic acute phase response, which occurs during the immediate early stages of liver regeneration. Analysis of cDNA expression arrays identified a number of genes such as immediate early transcription factors (ID-3, Stat3, Nur77), matrix metalloproteinase-9 (MMP-9), and several glutathione S-transferase (GST) isoforms and stress response genes, whose expression is elevated in regenerating TTR-FoxM1B TG livers compared with regenerating wild-type (WT) liver. These liver regeneration studies demonstrate that hepatocyte nuclear translocation of the FoxM1B transgene protein was sustained for the first 6 h after PHx, and was associated with transient hypertrophy of regenerating TG hepatocytes and increased expression of genes that may enhance hepatocyte proliferation.

Animals↗
PubMed2005

Synergistic effect of keratinocyte transplantation and epidermal growth factor delivery on epidermal regeneration.

Both keratinocyte transplantation and epidermal growth factor (EGF) delivery stimulate epidermal regeneration. In this study, we hypothesized that the combined therapy of keratinocyte transplantation and EGF delivery accelerates epidermal regeneration compared to the single therapy of either keratinocyte transplantation or EGF delivery. To test this hypothesis, we utilized fibrin matrix as a keratinocyte/EGF delivery vehicle for epidermal regeneration. Full-thickness wounds were created on the dorsum of athymic mice, and human keratinocytes and EGF in fibrin matrix were sprayed onto the wounds to regenerate epidermal layers (group 1). As controls, human keratinocytes in fibrin matrix (group 2), EGF in fibrin matrix (group 3), or fibrin matrix alone (group 4) was sprayed onto the wounds. Spraying keratinocytes suspended in fibrin matrix did not affect the keratinocyte viability, as the cell viabilities before and after spraying were not different. EGF was released from fibrin matrix for 3 days. The wounds were analyzed with histology and immunohistochemistry at 1 and 3 weeks after treatments. Compared with the control groups, initial wound closure rate was highest in group 1. Histological analyses indicated that group 1 exhibited faster and better epidermal regeneration than the other groups. Immunohistochemical analyses showed that regenerated epithelium in groups 1 and 2 stained positively for human involucrin at 3 weeks, whereas the tissue sections of the groups 3 and 4 stained negatively. Human laminin was detected at the dermal-epidermal junction of the regenerated tissues in groups 1 and 2 at 3 weeks and was not detected in groups 3 and 4. The epidermal thickness of the regenerated tissues in group 1 was significantly thicker than that of the other groups at all time points. These results suggest that the combined therapy of keratinocyte transplantation and EGF delivery is more efficacious for epidermal regeneration than each separate therapy alone.

Animals↗
PubMed2006

Expression patterns and action analysis of genes associated with blood coagulation responses during rat liver regeneration.

AIM: To study the blood coagulation response after partial hepatectomy (PH) at transcriptional level. METHODS: After PH of rats, the associated genes with blood coagulation were obtained through reference to the databases, and the gene expression changes in rat regenerating liver were analyzed by the Rat Genome 230 2.0 array. RESULTS: It was found that 107 genes were associated with liver regeneration. The initially and totally expressing gene numbers occurring in initiation phase of liver regeneration (0.5-4 h after PH), G0/G1 transition (4-6 h after PH), cell proliferation (6-66 h after PH), cell differentiation and structure-function reconstruction (66-168 h after PH) were 44, 11, 58, 7 and 44, 33, 100, 71 respectively, showing that the associated genes were mainly triggered in the forepart and prophase, and worked at different phases. According to their expression similarity, these genes were classified into 5 groups: only up-, predominantly up-, only down-, predominantly down-, up- and down-regulation, involving 44, 8, 36, 13 and 6 genes, respectively, and the total times of their up- and down-regulation expression were 342 and 253, respectively, demonstrating that the number of the up-regulated genes was more than that of the down-regulated genes. Their time relevance was classified into 15 groups, showing that the cellular physiological and biochemical activities were staggered during liver regeneration. According to gene expression patterns, they were classified into 29 types, suggesting that their protein activities were diverse and complex during liver regeneration. CONCLUSION: The blood coagulation response is enhanced mainly in the forepart, prophase and anaphase of liver regeneration, in which the response in the forepart, prophase of liver regeneration can prevent the bleeding caused by partial hepatectomy, whereas that in the anaphase contributes to the structure-function reorganization of regenerating liver. In the process, 107 genes associated with liver regeneration play an important role.

Animals↗