scholarly journals Keratin5-BMP4 Mechanosignaling Network Regulates Cell Cytoskeletal Reorganization and Chromatin Accessibility during Revascularization-Based Blastema Regeneration

2021 ◽  
Author(s):  
Xuelong Wang ◽  
Huiping Guo ◽  
Feifei Yu ◽  
Hui Zhang ◽  
Ying Peng ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Chromatin Remodeling ◽  
Chromatin Accessibility ◽  
Heart Regeneration ◽  
Regenerative Processes ◽  
Embryonic Fibroblasts ◽  
Nuclear Reorganization ◽  
Spatiotemporal Expression ◽  
Cell Remodeling ◽  
Zebrafish Heart

Heart regeneration after myocardial infarction remains challenging in reconstruction of blood resupply system. Here, we find that in zebrafish heart after resection of the ventricular apex, the local myocardial cells and the clotted blood cells undergo cell remodeling process via cytoplasmic exocytosis and nuclear reorganization within revascularization-based blastema. The regenerative processes are visualized by spatiotemporal expression of three blastema representative factors (alpha-SMA- which marks for fibrogenesis, Flk1for angiogenesis/hematopoiesis, and Pax3a for remusculogensis)，and two histone modifications (H3K9Ac and H3K9Me3 mark for chromatin remodeling). Using the cultured zebrafish embryonic fibroblasts we identify blastema fraction components and show that Krt5 peptide could link cytoskeleton network and BMP4 signaling pathway to regulate the transcription and chromatin accessibility at the blastema representative genes and bmp4 genes. Our study provides new mechanistic insights into the epithelial-dependent and revascularization-based blastema regeneration for potential myocardial infarction therapy.

scholarly journals Keratin5-BMP4 mechanosignaling regulates reciprocal acetylation and methylation at H3K9 to define blastema cell remodeling during zebrafish heart regeneration

2020 ◽  
Author(s):  
Xuelong Wang ◽  
Huiping Guo ◽  
Feifei Yu ◽  
Wei Zheng ◽  
Hui Zhang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ischemia Reperfusion Injury ◽  
Blood Clot ◽  
Ischemia Reperfusion ◽  
Subcellular Fractions ◽  
Heart Regeneration ◽  
Blastema Cell ◽  
Therapy Strategy ◽  
Cell Remodeling ◽  
Extracellular Molecules

AbstractHeart regeneration after myocardial infarction remains challenging due to scar and ischemia-reperfusion injury. Here, we show that zebrafish blastema regeneration can effectively resalvage the wound myocardium and blood clot through cytoplasmic exocytosis and nuclear reorganization. The cell remodeling process are also visualized by spatiotemporal expression of three core blastema genes: alpha-SMA- which marks for fibrogenesis, Flk1for angiogenesis/hematopoiesis, Pax3a for remusculogensis, and by characteristic chromatin depositions of H3K9Ac/H3K9Me3. Genome-wide enhancer identification links the depositions of the two histone marks to the chromatin state and these three core blastema cell phenotypes. When the blastema subcellular fractions are introduced into the cultured zebrafish embryonic fibroblasts the altered transcription profile is comparable to the blastema transcription in terms of extracellular matrix structural constituent, vasculature development/angiogenesis, and cardiac muscle regeneration. From the subcellular fractions we identify 15 extracellular components and intermediate filaments, and show that introduction of human Krt5 and noggin peptides conversely regulate PAC2 cells F-actin reorganization, chromatin depositions of H3K9Ac/ H3K9Me3 and phosphorylation of Smad, which are accompanied by characteristic transcriptions of bmp, bmp4, three core blastema genes as well as specific histone acetylation/methylation-related genes. Collectively, this study establishes a new Krt5-BMP4 mechanosignaling cascade that links extracellular molecules to chromatin modifications and regulates blastema cell remodeling, thus providing mechanistic insights into the mesoderm-derived blastema regeneration and underlining a therapy strategy for myocardial infarction.

scholarly journals Inhibition of let-7c Regulates Cardiac Regeneration after Cryoinjury in Adult Zebrafish

2019 ◽  
Vol 6 (2) ◽  
pp. 16 ◽  
Author(s):  
Suneeta Narumanchi ◽  
Karri Kalervo ◽  
Sanni Perttunen ◽  
Hong Wang ◽  
Katariina Immonen ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Regeneration ◽  
Nuclear Antigen ◽  
Heart Regeneration ◽  
Adult Zebrafish ◽  
Tissue Samples ◽  
Micro Rnas ◽  
Proliferating Cell ◽  
Zebrafish Heart

The let-7c family of micro-RNAs (miRNAs) is expressed during embryonic development and plays an important role in cell differentiation. We have investigated the role of let-7c in heart regeneration after injury in adult zebrafish. let-7c antagomir or scramble injections were given at one day after cryoinjury (1 dpi). Tissue samples were collected at 7 dpi, 14 dpi and 28 dpi and cardiac function was assessed before cryoinjury, 1 dpi, 7 dpi, 14 dpi and 28 dpi. Inhibition of let-7c increased the rate of fibrinolysis, increased the number of proliferating cell nuclear antigen (PCNA) positive cardiomyocytes at 7 dpi and increased the expression of the epicardial marker raldh2 at 7 dpi. Additionally, cardiac function measured with echocardiography recovered slightly more rapidly after inhibition of let-7c. These results reveal a beneficial role of let-7c inhibition in adult zebrafish heart regeneration.

scholarly journals Cardiac cell–integrated microneedle patch for treating myocardial infarction

2018 ◽  
Vol 4 (11) ◽  
pp. eaat9365 ◽  
Author(s):  
Junnan Tang ◽  
Jinqiang Wang ◽  
Ke Huang ◽  
Yanqi Ye ◽  
Teng Su ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stromal Cells ◽  
Heart Regeneration ◽  
Patch Application ◽  
Model Study ◽  
Heart Repair ◽  
Injured Myocardium ◽  
Cardiac Functions ◽  
Microneedle Patch ◽  
Host Myocardium

We engineered a microneedle patch integrated with cardiac stromal cells (MN-CSCs) for therapeutic heart regeneration after acute myocardial infarction (MI). To perform cell-based heart regeneration, cells are currently delivered to the heart via direct muscle injection, intravascular infusion, or transplantation of epicardial patches. The first two approaches suffer from poor cell retention, while epicardial patches integrate slowly with host myocardium. Here, we used polymeric MNs to create “channels” between host myocardium and therapeutic CSCs. These channels allow regenerative factors secreted by CSCs to be released into the injured myocardium to promote heart repair. In the rat MI model study, the application of the MN-CSC patch effectively augmented cardiac functions and enhanced angiomyogenesis. In the porcine MI model study, MN-CSC patch application was nontoxic and resulted in cardiac function protection. The MN system represents an innovative approach delivering therapeutic cells for heart regeneration.

scholarly journals Myogenic MicroRNA Expression Requires ATP-Dependent Chromatin Remodeling Enzyme Function

2010 ◽  
Vol 30 (13) ◽  
pp. 3176-3186 ◽  
Author(s):  
Chandrashekara Mallappa ◽  
Brian T. Nasipak ◽  
Letitiah Etheridge ◽  
Elliot J. Androphy ◽  
Stephen N. Jones ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Ex Vivo ◽  
Chromatin Accessibility ◽  
Microrna Expression ◽  
Atpase Subunit ◽  
Chromatin Remodelers ◽  
Actin Organization ◽  
Microrna Gene ◽  
Tissue Culture Model ◽  
Microrna Processing

ABSTRACT Knockdown of the Brg1 ATPase subunit of SWI/SNF chromatin remodeling enzymes in developing zebrafish caused stunted tail formation and altered sarcomeric actin organization, which phenocopies the loss of the microRNA processing enzyme Dicer, or the knockdown of myogenic microRNAs. Furthermore, myogenic microRNA expression and differentiation was blocked in Brg1 conditional myoblasts differentiated ex vivo. The binding of Brg1 upstream of myogenic microRNA sequences correlated with MyoD binding and accessible chromatin structure in satellite cells and myofibers, and it was required for chromatin accessibility and microRNA expression in a tissue culture model for myogenesis. The results implicate ATP-dependent chromatin remodelers in myogenic microRNA gene regulation.

Abstract 706: Changes in Translational Efficacy During Zebrafish Heart Regeneration

2019 ◽  
Vol 125 (Suppl_1) ◽  
Author(s):  
Joseph A Goldman ◽  
Ariel Bazzini ◽  
Antonio Giraldez ◽  
Kenneth Poss
Keyword(s):  
Heart Regeneration ◽  
Zebrafish Heart

scholarly journals Nuclear Heparanase Regulates Chromatin Remodeling, Gene Expression and PTEN Tumor Suppressor Function

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2038
Author(s):  
Rada Amin ◽  
Kaushlendra Tripathi ◽  
Ralph D. Sanderson
Keyword(s):  
Tumor Suppressor ◽  
Chromatin Remodeling ◽  
Target Genes ◽  
Myeloma Cell ◽  
Chromatin Accessibility ◽  
Tumor Suppressor Function ◽  
Suppressor Activity ◽  
Downstream Target ◽  
Suppressor Function ◽  
Chromatin Opening

Heparanase (HPSE) is an endoglycosidase that cleaves heparan sulfate and has been shown in various cancers to promote metastasis, angiogenesis, osteolysis, and chemoresistance. Although heparanase is thought to act predominantly extracellularly or within the cytoplasm, it is also present in the nucleus, where it may function in regulating gene transcription. Using myeloma cell lines, we report here that heparanase enhances chromatin accessibility and confirm a previous report that it also upregulates the acetylation of histones. Employing the Multiple Myeloma Research Foundation CoMMpass database, we demonstrate that patients expressing high levels of heparanase display elevated expression of proteins involved in chromatin remodeling and several oncogenic factors compared to patients expressing low levels of heparanase. These signatures were consistent with the known function of heparanase in driving tumor progression. Chromatin opening and downstream target genes were abrogated by inhibition of heparanase. Enhanced levels of heparanase in myeloma cells led to a dramatic increase in phosphorylation of PTEN, an event known to stabilize PTEN, leading to its inactivity and loss of tumor suppressor function. Collectively, this study demonstrates that heparanase promotes chromatin opening and transcriptional activity, some of which likely is through its impact on diminishing PTEN tumor suppressor activity.

scholarly journals In vivo cardiac reprogramming contributes to zebrafish heart regeneration

Nature ◽  
2013 ◽  
Vol 498 (7455) ◽  
pp. 497-501 ◽  
Author(s):  
Ruilin Zhang ◽  
Peidong Han ◽  
Hongbo Yang ◽  
Kunfu Ouyang ◽  
Derek Lee ◽  
...  
Keyword(s):  
Heart Regeneration ◽  
Zebrafish Heart

Cardiomyocyte proliferation in cardiac development and regeneration: a guide to methodologies and interpretations

2015 ◽  
Vol 309 (8) ◽  
pp. H1237-H1250 ◽  
Author(s):  
Marina Leone ◽  
Ajit Magadum ◽  
Felix B. Engel
Keyword(s):  
Cardiac Function ◽  
Molecular Mechanisms ◽  
Cardiac Development ◽  
Cardiac Regeneration ◽  
Experimental Medicine ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Naturally Occurring ◽  
Ability To Regenerate ◽  
Zebrafish Heart

The newt and the zebrafish have the ability to regenerate many of their tissues and organs including the heart. Thus, a major goal in experimental medicine is to elucidate the molecular mechanisms underlying the regenerative capacity of these species. A wide variety of experiments have demonstrated that naturally occurring heart regeneration relies on cardiomyocyte proliferation. Thus, major efforts have been invested to induce proliferation of mammalian cardiomyocytes in order to improve cardiac function after injury or to protect the heart from further functional deterioration. In this review, we describe and analyze methods currently used to evaluate cardiomyocyte proliferation. In addition, we summarize the literature on naturally occurring heart regeneration. Our analysis highlights that newt and zebrafish heart regeneration relies on factors that are also utilized in cardiomyocyte proliferation during mammalian fetal development. Most of these factors have, however, failed to induce adult mammalian cardiomyocyte proliferation. Finally, our analysis of mammalian neonatal heart regeneration indicates experiments that could resolve conflicting results in the literature, such as binucleation assays and clonal analysis. Collectively, cardiac regeneration based on cardiomyocyte proliferation is a promising approach for improving adult human cardiac function after injury, but it is important to elucidate the mechanisms arresting mammalian cardiomyocyte proliferation after birth and to utilize better assays to determine formation of new muscle mass.

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