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PubMed1992

Identification of proteins potentially involved in proximal-distal pattern formation in the regenerating forelimb of the newt.

We have used high resolution two-dimensional gel electrophoresis to identify and characterize proteins that may represent products of genes involved in establishing positional information along the proximal-distal axis of the regenerating forelimb of the newt Notophthalmus viridescens. At least 24 proteins have been found whose synthesis and (or) abundance is increased in proximal (midstylopodial) regenerates relative to midzeugopodial (distal) regenerates at either of two regeneration stages, the early dedifferentiation and moderate bud stages. Four of these same proteins show an axial asymmetry at both stages. Ten distal-specific proteins were also identified, although only one was common to both stages. More significantly, 6 of these 34 proteins (molecular masses of 73, 73, 51.5, 44.0, 19.5, and 16.5 kilodaltons and isoelectric points of 6.70, 6.74, 6.0, 6.05, 5.9, and 6.98, respectively) are regulated to proximal levels by treatment of distal regenerates with retinoic acid (RA) at both stages. An additional five are proximalized by RA at only one regeneration stage. Since the effect of RA is to proximalize positional information in blastema cells, these 11 proteins represent gene products that could be involved in a biochemical cascade leading to the establishment of positional information in the regenerating limb along this axis.

Animals↗
PubMed2003

p21 is essential for normal myogenic progenitor cell function in regenerating skeletal muscle.

Despite the ability of myogenic progenitor cells (MPCs) to completely regenerate skeletal muscle following injury, little is known regarding the molecular program that regulates their proliferation and differentiation. Although mice lacking the cyclin-dependent kinase inhibitor p21 (p21-/-), develop normally, we report here that p21-/- MPCs display increased cell number and enhanced cell cycle progression compared with wild-type MPCs. Therefore, we hypothesized that p21-/- mice would demonstrate temporally enhanced regeneration following myotrauma. In response to cardiotoxin-induced injury, p21-/- skeletal muscle regeneration was significantly attenuated vs. regenerating wild-type muscle, contrary to the hypothesis. Regenerating p21-/- skeletal muscle displayed increased proliferative (PCNA positive) nuclei coincident with increased apoptotic nuclei (TUNEL positive) compared with wild-type muscle up to 3 wk after injury. Differentiation of p21-/- MPCs was markedly impaired and associated with increased apoptosis compared with wild-type MPCs, confirming that the impaired differentiation of the p21-/- MPCs was a cell autonomous event. No dysregulation of p27, p53, or p57 protein expression in differentiating p21-/- MPCs compared with wild-type MPCs was observed, suggesting that other compensatory mechanisms are responsible for the regeneration that ultimately occurs. On the basis of these findings, we propose that p21 is essential for the coordination of cell cycle exit and differentiation in the adult MPC population and that in the absence of p21, skeletal muscle regeneration is markedly impaired.

Animals↗
PubMed2005

Rad is temporally regulated within myogenic progenitor cells during skeletal muscle regeneration.

The successful use of myogenic progenitor cells for therapeutic applications requires an understanding of the intrinsic and extrinsic cues involved in their regulation. Herein we demonstrate the expression pattern and transcriptional regulation of Rad, a prototypical member of a family of novel Ras-related GTPases, during mammalian development and skeletal muscle regeneration. Rad was identified using microarray analysis, which revealed robust upregulation of its expression during skeletal muscle regeneration. Our current findings demonstrate negligible Rad expression with resting adult skeletal muscle; however, after muscle injury, Rad is expressed within the myogenic progenitor cell population. Rad expression is significantly increased and localized to the myogenic progenitor cell population during the early phases of regeneration and within the newly regenerated myofibers during the later phases of regeneration. Immunohistochemical analysis demonstrated that Rad and MyoD are coexpressed within the myogenic progenitor cell population of regenerating skeletal muscle. This expression profile of Rad during skeletal muscle regeneration is consistent with the proposed roles for Rad in the inhibition of L-type Ca(2+) channel activity and the inhibition of Rho/RhoA kinase activity. We also have demonstrated that known myogenic transcription factors (MEF2, MyoD, and Myf-5) can increase the transcriptional activity of the Rad promoter and that this ability is significantly enhanced by the presence of the Ca(2+)-dependent phosphatase calcineurin. Furthermore, this enhanced transcriptional activity appears to be dependent on the presence of a conserved NFAT binding motif within the Rad promoter. Taken together, these data define Rad as a novel factor within the myogenic progenitor cells of skeletal muscle and identify key regulators of its transcriptional activity.

Animals↗
PubMed2005

Mice deficient in plasminogen activator inhibitor-1 have improved skeletal muscle regeneration.

Skeletal muscle possesses a remarkable capacity for regeneration. Although the regulation of this process at the molecular level remains largely undefined, the plasminogen system appears to play a critical role. Specifically, mice deficient in either urokinase-type plasminogen activator (uPA-/- mice) or plasminogen demonstrate markedly impaired muscle regeneration after injury. In the present study, we tested the hypothesis that loss of the primary inhibitor of uPA, plasminogen activator inhibitor-1 (PAI-1), would improve muscle regeneration. Repair of the extensor digitorum longus muscle was assessed after cardiotoxin injury in wild-type, uPA-/-, and PAI-1-deficient (PAI-1-/-) mice. As expected, there was no uPA activity in the injured muscles of uPA-/- mice, and muscles from these transgenic animals demonstrated impaired regeneration. On the other hand, uPA activity was increased in injured muscle from PAI-1-/- mice to a greater extent than in wild-type controls. Furthermore, PAI-1-/- mice demonstrated increased expression of MyoD and developmental myosin after injury as well as accelerated recovery of muscle morphology, protein levels, and muscle force compared with wild-type animals. The injured muscles of PAI-1-null mice also demonstrated increased macrophage accumulation, contrasting with impaired macrophage accumulation in uPA-deficient mice. The extent of macrophage accumulation correlated with both the clearance of protein after injury and the efficiency of regeneration. Taken together, these results indicate that PAI-1 deficiency promotes muscle regeneration, and this protease inhibitor represents a therapeutic target for enhancing muscle regeneration.

Animals↗
PubMed2003

Expression of SERCA2a is independent of innervation in regenerating soleus muscle.

The speed of contraction of a skeletal muscle largely depends on the myosin heavy chain isoforms (MyHC), whereas the relaxation is initiated and maintained by the sarcoplasmic reticulum Ca2+-ATPases (SERCA). The expression of the slow muscle-type myosin heavy chain I (MyHCI) is entirely dependent on innervation, but, as we show here, innervation is not required for the expression of the slow-type sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) in regenerating soleus muscles of the rat, although it can play a modulator role. Remarkably, the SERCA2a level is even higher in denervated than in innervated regenerating soleus muscles on day 7 when innervation is expected to resume. Later, the level of SERCA2a protein declines in denervated regenerated muscles but it remains expressed, whereas the corresponding mRNA level is still increasing. SERCA1 (i.e., the fast muscle-type isoform) expression shows only minor changes in denervated regenerating soleus muscles compared with innervated regenerating controls. When the soleus nerve was transected instead of the sciatic nerve, SERCA2a and MyHCI expressions were found to be even more uncoupled because the MyHCI nearly completely disappeared, whereas the SERCA2a mRNA and protein levels decreased much less. The transfection of regenerating muscles with constitutively active mutants of the Ras oncogene, known to mimic the effect of innervation on the expression of MyHCI, did not affect SERCA2a expression. These results demonstrate that the regulation of SERCA2a expression is clearly distinct from that of the slow myosin in the regenerating soleus muscle and that SERCA2a expression is modulated by neuronal activity but is not entirely dependent on it.

Animals↗
PubMed1993

Expression of hepatocyte growth factor in growing and regenerating rat skeletal muscle.

The expression of hepatocyte growth factor (HGF) was studied in rat skeletal muscle during postnatal growth and during regeneration after ischemic injury. By Northern blot analysis two RNA transcripts with estimated sizes of 6.0 and 3.1 kb, respectively, could be detected in immature skeletal muscle at 2, 4, and 10 days after birth, whereas no signal could be detected in adult skeletal muscle. In regenerating muscle, HGF mRNA was reexpressed, and a distinct signal was evident during the first days after the injury. One week after the injury only a weak signal was obtained. By in situ hybridization staining, HGF mRNA could be demonstrated in the immature muscle tissue of newborn rats but not in adult skeletal muscle. In regenerating muscle, the staining for HGF mRNA could be demonstrated in the regenerating muscle cells during the early phase of the regeneration. One week after the injury, only faint staining for HGF mRNA persisted in the regenerated fibers. It is concluded that HGF expression is developmentally regulated in skeletal muscle and that HGF is reexpressed in a transient manner during postischemic muscle regeneration.

Animals↗
PubMed1996

Endurance training affects myosin heavy chain phenotype in regenerating fast-twitch muscle.

The aim of this study was to analyze the effects of treadmill training (2 h/day, 5 days/wk, 30 m/min, 7% grade for 5 wk) on the expression of myosin heavy chain (MHC) isoforms during and after regeneration of a fast-twitch white muscle [extensor digitorum longus (EDL)]. Male Wistar rats were randomly assigned to a sedentary (n = 10) or an endurance-trained (ET; n = 10) group. EDL muscle degeneration and regeneration were induced by two subcutaneous injections of a snake toxin. Five days after induction of muscle injury, animals were trained over a 5-wk period. It was verified that approximately 40 days after venom treatment, central nuclei were present in the treated EDL muscles from sedentary and ET rats. The changes in the expression of MHCs in EDL muscles were detected by using a combination of biochemical and immunocytochemical approaches. Compared with contralateral nondegenerated muscles, relative concentrations of types I, IIa, and IIx MHC isoforms in ET rats were greater in regenerated EDL muscles (146%, P < 0.05; 76%, P < 0.01; 87%, P < 0.01, respectively). Their elevation corresponded to a decrease in the relative concentration of type IIb MHC (-36%, P < 0.01). Although type I accounted for only 3.2% of total myosin in regenerated muscles from the ET group, the cytochemical analysis showed that the proportion of positive staining with the slow MHC antibody was markedly greater in regenerated muscles than in contralateral ones. Collectively, these results demonstrate that the regenerated EDL muscle is sensitive to endurance training and suggest that the training-induced shift in MHC isoforms observed in these muscles resulted from an additive effect of regeneration and repeated exercise.

Animals↗
PubMed2000

Regeneration of cerebral-buccal interneurons and recovery of ingestion buccal motor programs in Aplysia after CNS lesions.

In the sea slug Aplysia, rhythmic biting is eliminated after bilateral cerebral-buccal connective (CBC) crushes and recovers within 14 days postlesion (dpl). The ability of cerebral-buccal interneuron-2 (CBI-2) to elicit ingestion buccal motor programs (iBMPs; i.e., fictive rhythmic ingestion) and to regenerate synaptic connections with target buccal neurons was assessed with intracellular recordings and dye injections. Isolated central ganglia were obtained from control animals and from lesioned animals at selected times after bilateral CBC crushes. Within 3 wk postlesion, transected CBI-2 axons sprouted at least 10 fine neurites confined to the core of the CBC that projected across the crush site toward the buccal ganglia. When fired with depolarizing current steps, CBI-2 was not observed to elicit iBMPs in preparations until 14 dpl. Thereafter a progressive enhancement in CBI-2's ability to elicit iBMPs was observed with time postlesion. By 40 dpl, CBI-2-elicited iBMPs were indistinguishable from those of controls. CBI-2 regenerated monosynaptic connections with appropriate buccal premotor- and motorneurons by 14 dpl, and the strength of these connections increased with time postlesion. Dramatic frequency facilitation was exhibited by the regenerating CBI-2 buccal synapses; for instance, at early postlesion times, no observable excitatory postsynaptic potentials (EPSPs) were obtained with 1- Hz stimulation of CBI-2, while at 7 Hz, a dramatic increase in EPSP amplitude was obtained with successive spikes. The present study shows that the time course of axonal and synaptic regeneration by command-like interneuron CBI-2 is correlated with the recovery of ingestion buccal motor programs elicited by CBI-2. These results parallel our previous findings of functional neural regeneration in the feeding system and suggest that functional neural regeneration is at least in part mediated by regeneration of specific synaptic pathways.

Animals↗
PubMedDate not supplied

Expression of Id-1 mRNA and protein in the post-ischemic regenerating rat kidney.

The basic helix-loop-helix (bHLH) class of proteins are of major importance in controlling tissue-specific gene expression. The actions of the bHLH proteins are inhibited by a related class of proteins, inhibitors of differentiation (Id). We have studied the expression of one of these latter proteins, Id-1, in the normal and post-ischemic regenerating rat kidney by immunocytochemistry, Western blot and RNase protection assay (RPA) and correlated Id-1 regulation to the expression of vimentin and proliferating cellular nuclear antigen (PCNA). In the normal kidney strong immunostaining for Id-1 was found in the distal nephron, especially in the distal convoluted tubule in the cortex. In particular, the perinuclear region was intensely stained in the cells of the distal tubule. mRNA for Id-1I was detectable by RPA on total RNA extracted from the renal cortex of sham-operated animals. The Id-1 monomer was detected on Western blots of normal animals. Vimentin was expressed in the mesangial cells of the glomeruli and in cells in the interstitium while tubule cells were negative. The labeling intensity for PCNA was low in all cellular compartments in the normal kidney. In the regenerating kidneys at various time intervals, the expression of Id-1-like immunoreactivity was widespread in the regenerating dedifferentiated tubule cells while by the end of the study period, more highly differentiated tubule cells appeared to lose their staining. On Western blots the Id-1 monomer was undetectable and instead strong staining was seen in the high molecular range. Id-1 mRNA levels in the regenerating kidneys did not differ significantly when compared to sham. PCNA labeling was intense in the regenerating kidneys at all time periods studied, indicating the intense proliferative activity in the regenerating kidneys. Vimentin expression in the renal tubule cells was increased from day 3 and onward. The data are consistent with a hypothesis in which Id-1 regulates differentiation of renal tubule cells in the post-ischemic regenerating rat kidney.

Animals↗
PubMed2004

Role of potassium channels in the frequency-dependent activity of regenerating nerves.

After a peripheral nerve injury, ion channel organization and the electrical properties of nerve fibers drastically change during the regeneration process. The present study was designed to compare the frequency-dependent characteristics of regenerating nerves in the presence of 4-aminopyridine (4-AP) and tetraethylammonium (TEA). The results showed that increasing the stimulus frequency produced a greater impulse blockade (frequency-dependent block--FDB) and distinct hyperpolarizing afterpotentials (HAPs) in regenerating nerves. In particular, regenerating sciatic nerves 15 days post-crush (dpc) were more sensitive to the frequency-dependent stimulations than 38-dpc and intact nerves in the presence or absence of drugs. The frequency-dependent effects of TEA on the compound action potentials (CAPs) appeared when TEA was applied to 4-AP-treated nerves. This shows that TEA-sensitive channels may not be masked by the myelin. 4-AP was here found to have more pronounced frequency-dependent effects on regenerating nerves than on intact nerves. Delayed depolarization (in 38-dpc: 22.6 +/- 1.3 mV and 47.52 +/- 3.63 ms, in intact: 12.0 +/- 1.9 mV and 88.51 +/- 4.72 ms) elicited by 4-AP resulted in an increase in FDBs and HAP amplitudes. These results suggest that 4-AP-sensitive channels may play important roles in frequency-dependent nerve conduction. Consequently, regenerating or myelin damaged nerves are more sensitive to repetitive firing with or without drug. An understanding of the frequency-dependent properties of regenerating nerves may be of value in the treatment of the nerve diseases.

Action Potentials↗
PubMed1992

Decrease in regeneration capacity of rat liver after external biliary drainage.

In order to discover the effect of external biliary drainage on liver regeneration, we have produced a model system carrying cannula in the common bile duct of rat liver and examined the regeneration capacity of liver after partial hepatectomy under various conditions. Previously we have shown that hepatic cells proliferate by obstructive jaundice alone without partial hepatectomy [Terasaki et al; Jpn J Cancer Res 1991;82:170-175]. In the present study, we showed that DNA polymerase-alpha was induced by partial hepatectomy of rats suffering from obstructive jaundice and the induced level was similar to that of the normal regenerating liver. The level of DNA polymerase-alpha activity corresponded well to the liver regeneration capacity estimated by mitotic index. Contrary to our expectation, external biliary drainage for obstructive jaundice markedly suppressed the regeneration capacity of the remaining liver which was estimated by DNA polymerase-alpha activity, mitotic index and [3H]thymidine incorporation. The suppression may be due to the external biliary drainage itself because the liver regeneration of normal rats without jaundice was also suppressed by the biliary drainage. These results suggest that the external biliary drainage seriously suppresses the regeneration capacity of liver at least at the early stage of obstructive jaundice.

Animals↗
PubMed2003

Recurrent laryngeal nerve regeneration by tissue engineering.

The recurrent laryngeal nerve (RLN) does not regenerate well after it has been cut, and no current surgical methods achieve functional regeneration. Here, we evaluate the functional regeneration of the RLN after reconstruction using a biodegradable nerve conduit or an autologous nerve graft. The nerve conduit was made of a polyglycolic acid (PGA) tube coated with collagen. A 10-mm gap in the resected nerve was bridged by a PGA tube in 6 adult beagle dogs (group 1) and by an autologous nerve graft in 3 dogs (group 2). Fiberscopic observation revealed functional regeneration of the RLN in 4 of the 6 dogs in group 1. No regeneration of the RLN was observed in any dog in group 2. We also tested for axonal transport, and measured the compound muscle action potential. The RLN can be functionally regenerated with a PGA tube, which may act as a scaffold for the growth of regenerating axons.

Absorbable Implants↗
PubMed1998

Effects of thrombin and protease nexin-1 on peripheral nerve regeneration.

Thrombin and serine protease inhibitors such as protease nexin-1 (PN-1) have been implicated in neurite outgrowth activity. We compared rat sciatic nerve regeneration in 10-mm silicone tubes, bridging an 8-mm nerve gap, that were prefilled with thrombin (1.5 IU) and PN-1 (50 micrograms/mL or 1 mg/mL) to those filled with saline solution (control). Neural regeneration and fibrinoid matrix progression (deposition of extracellular matrix) were analyzed at 1, 4, 17, and 21 days after silicone tube implantation. At 1 and 4 days after implantation, thrombin reduced fibrinoid matrix length propagation from both the proximal and distal transected nerve stumps, but PN-1 and saline did not interfere with matrix progression (p < .05). Seventeen days after implantation, the number of silicone tubes containing myelinated neuronal regenerates at the mid-tube region was 1 of 6 for thrombin, 6 of 9 for PN-1, and 6 of 10 for saline solution. Twenty-one days after implantation, 11 of 11 tubes with saline solution, 9 of 11 with PN-1 at 1 mg/mL, and 7 of 9 with PN-1 at 50 micrograms/mL had myelinated neural regenerates in the mid-silicone tube region, while only 2 of 9 thrombin-containing silicone tubes contained myelinated axons. There was no statistically significant difference in myelinated neurite regenerates at 17 and 21 days after implantation among silicone tubes prefilled with saline solution and PN-1 (50 micrograms/mL or 1 mg/mL). Thrombin interfered with matrix progression and significantly reduced the number of myelinated neurite regenerates (p = .01). The PN-1 and saline solutions did not inhibit matrix progression or affect the number of myelinated axonal regenerates (p = .92).

Amyloid beta-Protein Precursor↗
PubMed2002

In vivo activation of STAT3 signaling in satellite cells and myofibers in regenerating rat skeletal muscles.

Although growth factors and cytokines play critical roles in skeletal muscle regeneration, intracellular signaling molecules that are activated by these factors in regenerating muscles have been not elucidated. Several lines of evidence suggest that leukemia inhibitory factor (LIF) is an important cytokine for the proliferation and survival of myoblasts in vitro and acceleration of skeletal muscle regeneration. To elucidate the role of LIF signaling in regenerative responses of skeletal muscles, we examined the spatial and temporal activation patterns of an LIF-associated signaling molecule, the signal transducer and activator transcription 3 (STAT3) proteins in regenerating rat skeletal muscles induced by crush injury. At the early stage of regeneration, activated STAT3 proteins were first detected in the nuclei of activated satellite cells and then continued to be activated in proliferating myoblasts expressing both PCNA and MyoD proteins. When muscle regeneration progressed, STAT3 signaling was no longer activated in differentiated myoblasts and myotubes. In addition, activation of STAT3 was also detected in myonuclei within intact sarcolemmas of surviving myofibers that did not show signs of necrosis. These findings suggest that activation of STAT3 signaling is an important molecular event that induces the successful regeneration of injured skeletal muscles.

Animals↗
PubMed1990

First place--Resident Basic Science Award 1990. Fibronectin-laminin combination enhances peripheral nerve regeneration across long gaps.

An exogenous fibronectin-laminin (FN-LAM) solution was added into silicone chambers to determine the effects on peripheral nerve regeneration across 18-mm long gaps. The sciatic nerves of adult rats were sutured into silicone chambers 20 mm in length, creating an 18-mm gap between the proximal and distal nerve stumps. The chambers were filled with either a mixture of fibronectin and laminin (500 micrograms/ml each) or a solution of cytochrome C (1 mg/ml) as the control. After six weeks, the animals were killed and the chambers were examined for regeneration. Seventy percent of the animals from the FN-LAM group demonstrated regeneration across the 18-mm gaps, compared to only 30% in the control group. The combination of FN-LAM significantly increased the number of axons that grew into the distal end of the chamber (FN-LAM, 1325 +/- 522; cytochrome C, 153 +/- 104; p = 0.03). Examination of the distal tributaries of the sciatic nerve revealed axons only in the FN-LAM group; none were found in the control group. Quantitative analysis of neurons, retrogradely labeled with horseradish peroxidase via injection of the sciatic nerve distal to the regenerated segment, revealed a greater number of sensory and motor neurons in the FN-LAM group compared to the control group. Morphometric studies revealed that the mean area of the regenerated segment in the FN-LAM group was 37% larger than the controls, and ultrastructural analysis demonstrated a more mature regenerated nerve. This is the first in vivo demonstration that this combination of fibronectin and laminin significantly enhances the regeneration of myelinated axons across a long nerve gap in the rat sciatic nerve.

Academies and Institutes↗
PubMed2005

Live imaging of regenerating lamprey spinal axons.

BACKGROUND: The sea lamprey has been used as a model for the study of axonal regeneration after spinal cord injury. Although the growing tips of developing axons in lamprey have not been described, in all species studied, growth cones are complex in shape, consisting of a lamellipodium and filopodia, rich in F-actin and lacking neurofilaments (NF). By contrast, static immunohistochemical and electron microscopic observations of fixed tissue suggested that the tips of regenerating lamprey spinal axons are simple in shape, densely packed with NF, but contain very little F-actin. Thus, it has been proposed that regeneration of axons in the CNS of mature animals is not based on the canonical pulling mechanism of growth cones but involves an internal protrusive force, perhaps generated by the transport and assembly of NF. To eliminate the possibility that these histological features are due to fixation artifact, fluorescently labeled regenerating axon tips were imaged live. METHODS: Spinal cords were transected, and after 0 to 10 weeks, the CNS was isolated in lamprey Ringer at 5 degrees C to 12 degrees C and the large reticulospinal axons were microinjected with fluorescent tracers. The proximal axon tips were imaged with a fluorescence dissecting microscope repeatedly over 2 to 5 days and photographed with confocal microscopy. Experiments were also performed through a dorsal incision in the living animal. Axon tips were microinjected as above or retrogradely labeled with tracer applied to the transection site and photographed through the fluorescence dissecting scope or with two-photon microscopy. The spinal cords were then fixed and processed for wholemount NF immunohistochemistry. RESULTS: The living axon tips were simple in shape, not significantly different from those in fixed spinal cords, and filled with NF. In isolated CNS preparations, very little axon retraction and no regeneration was observed. In the living animal, rapid retraction, up to 3 mm/day, was seen during the 1st few days posttransection. At more than 2 weeks posttransection, some fibers showed regeneration of up to 35 microm/day. CONCLUSIONS: 1) The tips of regenerating lamprey axons are simple in shape and filled with NF. 2) Both axon retraction and axon extension are active processes, requiring factors present in the living animal that are missing in the isolated CNS.

Actins↗
PubMed2002

Spinal cord regeneration induced by a voltage-gated calcium channel agonist.

Regeneration in the central nervous system (CNS) is prohibitive. This is likely due to an interplay of cellular (gene expression, growth factors) and environmental (inhibition by CNS myelin) factors. Calcium supports various intracellular functions, and multiple in vitro studies have shown a role of calcium in axonal growth. In this study, we examine the role of a calcium agonist, S(-)-Bay K 8644, in promoting or impeding CNS growth in vivo, in an effort to understand further the relationship between the voltage-gated L type calcium channel and regeneration. Using a well-established rat spinal cord model of regeneration, we have injected various doses of S(-)-Bay K 8644 (30-240 M) around the injured spinal cord. Our results demonstrate that S(-)-Bay K 8644 enhances regeneration in a dose-dependent fashion. In addition, at very specific concentrations, the same agonist has no effect on or even inhibits regeneration. We conclude that spinal regeneration is highly dependent on intracellular calcium concentration. Furthermore, depending on the dose used, the effect of calcium agonist supplementation on spinal regeneration can be supportive or inhibitory.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2001

Urokinase-dependent plasminogen activation is required for efficient skeletal muscle regeneration in vivo.

Plasminogen activators urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) are extracellular proteases involved in various tissue remodeling processes. A requirement for uPA activity in skeletal myogenesis was recently demonstrated in vitro. The role of plasminogen activators in skeletal muscle regeneration in vivo in wild-type, uPA-deficient, and tPA-deficient mice is investigated here. Wild-type and tPA-/- mice completely repaired experimentally damaged skeletal muscle. In contrast, uPA-/- mice had a severe regeneration defect, with decreased recruitment of blood-derived monocytes to the site of injury and with persistent myotube degeneration. In addition, uPA-deficient mice accumulated fibrin in the degenerating muscle fibers; however, the defibrinogenation of uPA-deficient mice resulted in a correction of the muscle regeneration defect. A similar severe regeneration deficit with persistent fibrin deposition was also reproducible in plasminogen-deficient mice after injury, suggesting that fibrinolysis by uPA-mediated plasminogen activation plays a fundamental role in skeletal muscle regeneration. In conclusion, the uPA-plasmin system is identified as a critical component of the mammalian skeletal muscle regeneration process, possibly because it prevents intramuscular fibrin accumulation and contributes to the adequate inflammatory response after injury. These studies demonstrate the requirement of an extracellular proteolytic cascade during muscle regeneration in vivo.

Animals↗