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Igf Signaling is Required for Cardiomyocyte Proliferation during Zebrafish Heart Development and Regeneration  [PDF]
Ying Huang, Michael R. Harrison, Arthela Osorio, Jieun Kim, Aaron Baugh, Cunming Duan, Henry M. Sucov, Ching-Ling Lien
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0067266
Abstract: Unlike its mammalian counterpart, the adult zebrafish heart is able to fully regenerate after severe injury. One of the most important events during the regeneration process is cardiomyocyte proliferation, which results in the replacement of lost myocardium. Growth factors that induce cardiomyocyte proliferation during zebrafish heart regeneration remain to be identified. Signaling pathways important for heart development might be reutilized during heart regeneration. IGF2 was recently shown to be important for cardiomyocyte proliferation and heart growth during mid-gestation heart development in mice, although its role in heart regeneration is unknown. We found that expression of igf2b was upregulated during zebrafish heart regeneration. Following resection of the ventricle apex, igf2b expression was detected in the wound, endocardium and epicardium at a time that coincides with cardiomyocyte proliferation. Transgenic zebrafish embryos expressing a dominant negative form of Igf1 receptor (dn-Igf1r) had fewer cardiomyocytes and impaired heart development, as did embryos treated with an Igf1r inhibitor. Moreover, inhibition of Igf1r signaling blocked cardiomyocyte proliferation during heart development and regeneration. We found that Igf signaling is required for a subpopulation of cardiomyocytes marked by gata4:EGFP to contribute to the regenerating area. Our findings suggest that Igf signaling is important for heart development and myocardial regeneration in zebrafish.
Cardiomyocyte Regeneration  [PDF]
Nanako Kawaguchi,Toshio Nakanishi
Cells , 2013, DOI: 10.3390/cells2010067
Abstract: The heart was initially believed to be a terminally differentiated organ; once the cardiomyocytes died, no recovery could be made to replace the dead cells. However, around a decade ago, the concept of cardiac stem cells (CSCs) in adult hearts was proposed. CSCs differentiate into cardiomyocytes, keeping the heart functioning. Studies have proved the existence of stem cells in the heart. These somatic stem cells have been studied for use in cardiac regeneration. Moreover, recently, induced pluripotent stem cells (iPSCs) were invented, and methodologies have now been developed to induce stable cardiomyocyte differentiation and purification of mature cardiomyocytes. A reprogramming method has also been applied to direct reprogramming using cardiac fibroblasts into cardiomyocytes. Here, we address cardiomyocyte differentiation of CSCs and iPSCs. Furthermore, we describe the potential of CSCs in regenerative biology and regenerative medicine.
Regeneration of Cryoinjury Induced Necrotic Heart Lesions in Zebrafish Is Associated with Epicardial Activation and Cardiomyocyte Proliferation  [PDF]
Kristin Schnabel,Chi-Chung Wu,Thomas Kurth,Gilbert Weidinger
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0018503
Abstract: In mammals, myocardial cell death due to infarction results in scar formation and little regenerative response. In contrast, zebrafish have a high capacity to regenerate the heart after surgical resection of myocardial tissue. However, whether zebrafish can also regenerate lesions caused by cell death has not been tested. Here, we present a simple method for induction of necrotic lesions in the adult zebrafish heart based on cryoinjury. Despite widespread tissue death and loss of cardiomyocytes caused by these lesions, zebrafish display a robust regenerative response, which results in substantial clearing of the necrotic tissue and little scar formation. The cellular mechanisms underlying regeneration appear to be similar to those activated in response to ventricular resection. In particular, the epicardium activates a developmental gene program, proliferates and covers the lesion. Concomitantly, mature uninjured cardiomyocytes become proliferative and invade the lesion. Our injury model will be a useful tool to study the molecular mechanisms of natural heart regeneration in response to necrotic cell death.
Aberrant regeneration of the third cranial nerve  [PDF]
UD Shrestha,S Adhikari
Nepalese Journal of Ophthalmology , 2012, DOI: 10.3126/nepjoph.v4i1.5872
Abstract: Background : Aberrant regeneration of the third cranial nerve is most commonly due to its damage by trauma. Case : A ten-month old child presented with the history of a fall from a four-storey building. She developed traumatic third nerve palsy and eventually the clinical features of aberrant regeneration of the third cranial nerve. The adduction of the eye improved over time. She was advised for patching for the strabismic amblyopia as well. Conclusion : Traumatic third nerve palsy may result in aberrant regeneration of the third cranial nerve. In younger patients, motility of the eye in different gazes may improve over time. DOI: http://dx.doi.org/10.3126/nepjoph.v4i1.5872 NEPJOPH 2012; 4(1): 176-178
Pharmacological immunomodulation enhances peripheral nerve regeneration
Inoe, Ana Paula;Pereira, Francisco Carlos;Stopiglia, Angelo Jo?o;Da-Silva, Ciro Ferreira;
Pesquisa Veterinária Brasileira , 2007, DOI: 10.1590/S0100-736X2007000900002
Abstract: to assess the effect of n-acetylmuramyl-l-alanyl-d-isoglutamine mdp topically administrated on the regenerating peripheral neurons, twelve male c57bl/6j adult mice were equally distributed into three groups. four mice underwent unilateral sciatic nerve transection and polyethylene tubulization, with a 4mm gap between the proximal and distal nerve stumps and were implanted with collagen + pbs (col). other four animals underwent the same surgical procedure but received collagen + mdp (col/mdp) inside the prosthesis. four animals were not operated and served as control group (nor). after 4 weeks, the regenerated nerve cables were processed for total myelinated axon counting and myelinated fiber diameter measurement. the l5 dorsal root ganglion (drg) was also removed and sectioned for sensory neurons counting and measurement. the results revealed significant difference (p<0.05) in axonal counting among the groups nor (4,355±32), col (1,869±289) and col/mdp (2,430±223). there was a significant reduction in the axonal diameter in the operated groups (col=3.38μm±1.16 and col/mdp=3.54μm±1.16) compared to nor (6.19μm±2.45). no difference was found in the number of drg neurons between the experimental groups (col=564±51; col/mdp=514±56), which presented fewer sensory neurons compared to nor (1,097±142). data obtained indicate that locally applied mdp stimulates peripheral nerve regeneration in mice.
Nitroxyl (HNO) Stimulates Soluble Guanylyl Cyclase to Suppress Cardiomyocyte Hypertrophy and Superoxide Generation  [PDF]
Eliane Q. Lin, Jennifer C. Irvine, Anh H. Cao, Amy E. Alexander, Jane E. Love, Ruchi Patel, Julie R. McMullen, David M. Kaye, Barbara K. Kemp-Harper, Rebecca H. Ritchie
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034892
Abstract: Background New therapeutic targets for cardiac hypertrophy, an independent risk factor for heart failure and death, are essential. HNO is a novel redox sibling of NO? attracting considerable attention for the treatment of cardiovascular disorders, eliciting cGMP-dependent vasodilatation yet cGMP-independent positive inotropy. The impact of HNO on cardiac hypertrophy (which is negatively regulated by cGMP) however has not been investigated. Methods Neonatal rat cardiomyocytes were incubated with angiotensin II (Ang II) in the presence and absence of the HNO donor Angeli's salt (sodium trioxodinitrate) or B-type natriuretic peptide, BNP (all 1 μmol/L). Hypertrophic responses and its triggers, as well as cGMP signaling, were determined. Results We now demonstrate that Angeli's salt inhibits Ang II-induced hypertrophic responses in cardiomyocytes, including increases in cardiomyocyte size, de novo protein synthesis and β-myosin heavy chain expression. Angeli's salt also suppresses Ang II induction of key triggers of the cardiomyocyte hypertrophic response, including NADPH oxidase (on both Nox2 expression and superoxide generation), as well as p38 mitogen-activated protein kinase (p38MAPK). The antihypertrophic, superoxide-suppressing and cGMP-elevating effects of Angeli's salt were mimicked by BNP. We also demonstrate that the effects of Angeli's salt are specifically mediated by HNO (with no role for NO? or nitrite), with subsequent activation of cardiomyocyte soluble guanylyl cyclase (sGC) and cGMP signaling (on both cGMP-dependent protein kinase, cGK-I and phosphorylation of vasodilator-stimulated phosphoprotein, VASP). Conclusions Our results demonstrate that HNO prevents cardiomyocyte hypertrophy, and that cGMP-dependent NADPH oxidase suppression contributes to these antihypertrophic actions. HNO donors may thus represent innovative pharmacotherapy for cardiac hypertrophy.
Thyroid Hormones and Peripheral Nerve Regeneration  [PDF]
Ioannis D. Papakostas,George A. Macheras
Journal of Thyroid Research , 2013, DOI: 10.1155/2013/648395
Abstract: Peripheral nerve regeneration is a unique process in which cellular rather than tissue response is involved. Depending on the extent and proximity of the lesion and the age and type of the neuronal soma, the cell body may either initiate a reparative response or may die. Microsurgical intervention may alter the prognosis after a peripheral nerve injury but to a certain extent. By altering the biochemical microenvironment of the neuron, we can increase the proportion of neurons that survive the injury and initiate the reparative response. Thyroid hormone critically regulates tissue growth and differentiation and plays a crucial role during organ development. Furthermore, recent research has provided new insight into thyroid hormone cellular action. Thyroid hormone regulates stress response intracellular signaling and targets molecules important for cytoskeletal stability and cell integrity. Changes in thyroid hormone signaling occur in nerve and other tissues, with important physiological consequences. The interest in thyroid hormone in the context of nerve regeneration has recently been revived. 1. Introduction Thyroid hormones are essential for the development and maturation of the central nervous system. There is a period in brain development in which the euthyroid status is a prerequisite for normal development. Thyroid hormones promote morphogenesis and function in various areas of the brain. The molecular basis of the thyroid dependent brain development is not yet clarified [1]. Among other processes, defects in myelination, delays in the development of the dendritic tree, decreased number of glial cells, and axo-dendritic synapses have all been described in hypothyroid newborn rats. Peripheral nerve injuries are very common in the clinical setting [2]. These injuries are very debilitating, commonly affecting the younger more productive portion of the population. Microsurgical techniques to restore nerve continuity have reached their limits, and further surgical advancements in the field of peripheral nerve surgery are unlikely to improve the prognosis. A different approach based on the cellular and molecular aspects of regeneration should be followed [3]. This approach is justified by the fact that peripheral nerve injuries are in reality cellular, rather than tissue injuries. It is the long axon of the neuron that has been injured. In response, the cell body adapts in an effort to restore the cellular volume and function. Before adaptation the neuron should first survive from the index event. Apoptosis can be the fate of a large proportion of
Trypanosoma cruzi Coaxes Cardiac Fibroblasts into Preventing Cardiomyocyte Death by Activating Nerve Growth Factor Receptor TrkA  [PDF]
Daniel Aridgides, Ryan Salvador, Mercio PereiraPerrin
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0057450
Abstract: Rationale Cardiomyocytes express neurotrophin receptor TrkA that promotes survival following nerve growth factor (NGF) ligation. Whether TrkA also resides in cardiac fibroblasts (CFs) and underlies cardioprotection is unknown. Objective To test whether CFs express TrkA that conveys paracrine signals to neighbor cardiomyocytes using, as probe, the Chagas disease parasite Trypanosoma cruzi, which expresses a TrkA-binding neurotrophin mimetic, named PDNF. T cruzi targets the heart, causing chronic debilitating cardiomyopathy in ~30% patients. Methods and Results Basal levels of TrkA and TrkC in primary CFs are comparable to those in cardiomyocytes. However, in the myocardium, TrkA expression is significantly lower in fibroblasts than myocytes, and vice versa for TrkC. Yet T cruzi recognition of TrkA on fibroblasts, preferentially over cardiomyocytes, triggers a sharp and sustained increase in NGF, including in the heart of infected mice or of mice administered PDNF intravenously, as early as 3-h post-administration. Further, NGF-containing T cruzi- or PDNF-induced fibroblast-conditioned medium averts cardiomyocyte damage by H2O2, in agreement with the previously recognized cardioprotective role of NGF. Conclusions TrkA residing in CFs induces an exuberant NGF production in response to T cruzi infection, enabling, in a paracrine fashion, myocytes to resist oxidative stress, a leading Chagas cardiomyopathy trigger. Thus, PDNF-TrkA interaction on CFs may be a mechanism orchestrated by T cruzi to protect its heart habitat, in concert with the long-term (decades) asymptomatic heart parasitism that characterizes Chagas disease. Moreover, as a potent booster of cardioprotective NGF in vivo, PDNF may offer a novel therapeutic opportunity against cardiomyopathies.
Effect of Erythropoietin on Peripheral Nerve Regeneration
Journal of Neurological Sciences , 2010,
Abstract: The aim of this study was to identify the effect of erythropoietin (EPO) on a sciatic nerve injury model. The effect of single or repeated doses was also determined. Twenty-one Wistar rats were anesthetised and the sciatic nerve was transected 1 cm above the trifurcation and the nerve was repaired with four epineural 10/0 nylon sutures placed at 90 degrees intervals under microscope magnification.The rats were divided into 4 groups as follows: the sham,the saline, the single dose EPO and the multiple dose EPO. The skin was incised and closed and no treatment was given in sham group. In the saline group, 1 mL saline was given intraperitoneally; in the single EPO group, 5000 U/kg EPO was given intraperitoneally immediately after the procedure. In the multiple EPO group, 5000 U/kg EPO was given after the procedure and the same dose was repeated after the 1st, 2nd, 3rd and 4th weeks. Functional recovery was evaluated by static sciatic functional index(SSI).Single EPO group had greater myofibril size, axon number, diameter, and ratio M than the saline group. The multiple EPO treatment was not found to be more effective than single EPO treatment. However, no significant difference was found between the single EPO, multiple EPO, and saline groups based on the 3rd and 4th postoperative month SSI scores. Thus, EPO treatment increased axonal regeneration in our study. However, repeated dose therapy was not found to be more effective than single dose therapy. The optimum dose and duration should be researched in further studies.
Dilong: Role in Peripheral Nerve Regeneration
Yung-Ming Chang,Wei-Yi Chi,Tung-Yuan Lai,Yueh-Sheng Chen,Fuu-Jen Tsai,Chang-Hai Tsai,Wei-Wen Kuo,Yi-Chang Cheng,Chien-Chung Lin,Chih-Yang Huang
Evidence-Based Complementary and Alternative Medicine , 2011, DOI: 10.1093/ecam/neq079
Abstract: Dilong, also known as earthworm, has been widely used in traditional Chinese medicine (TCM) for thousands of years. Schwann cell migration and proliferation are critical for the regeneration of injured nerves and Schwann cells provide an essentially supportive role for neuron regeneration. However, the molecular mechanisms of migration and proliferation induced by dilongs in Schwann cells remain unclear. Here, we discuss the molecular mechanisms that includes (i) migration signaling, MAPKs (mitogen-activated protein kinases), mediated PAs and MMP2/9 pathway; (ii) survival and proliferative signaling, IGF-I (insulin-like growth factor-I)-mediated PI3K/Akt pathways and (iii) cell cycle regulation. Dilong stimulate RSC96 cell proliferation and migration. It can induce phosphorylation of ERK1/2 and p38, but not JNK, and activate the downstream signaling expression of PAs (plasminogen activators) and MMPs (matrix metalloproteinases) in a time-dependent manner. In addition, Dilong stimulated ERK1/2 and p38 phosphorylation was attenuated by pretreatment with chemical inhibitors (U0126 and SB203580), and small interfering ERK1/2 and p38 RNA, resulting in migration and uPA-related signal pathway inhibition. Dilong also induces the phosphorylation of IGF-I-mediated PI3K/Akt pathway, activates protein expression of PCNA (proliferating cell nuclear antigen) and cell cycle regulatory proteins (cyclin D1, cyclin E and cyclin A) in a time-dependent manner. In addition, it accelerates G1-phase progression with earlier S-phase entry and significant numbers of cells entered the S-phase. The siRNA-mediated knockdown of PI3K that significantly reduces PI3K protein expression levels, resulting in Bcl2 survival factor reduction, revealing a marked blockage of G1 to S transition in proliferating cells. These results reveal the unknown RSC96 cell migration and proliferation mechanism induced by dilong, which find use as a new medicine for nerve regeneration.
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