Engineering Extracellular Matrix Proteins to Enhance Cardiac Regeneration After Myocardial Infarction

Engineering microenvironments for accelerated myocardial repair is a challenging goal. Cell therapy has evolved over a few decades to engraft therapeutic cells to replenish lost cardiomyocytes in the left ventricle. However, compelling evidence supports that tailoring specific signals to endogenous cells rather than the direct integration of therapeutic cells could be an attractive strategy for better clinical outcomes. Of many possible routes to instruct endogenous cells, we reviewed recent cases that extracellular matrix (ECM) proteins contribute to enhanced cardiomyocyte proliferation from neonates to adults. In addition, the presence of ECM proteins exerts biophysical regulation in tissue, leading to the control of microenvironments and adaptation for enhanced cardiomyocyte proliferation. Finally, we also summarized recent clinical trials exclusively using ECM proteins, further supporting the notion that engineering ECM proteins would be a critical strategy to enhance myocardial repair without taking any risks or complications of applying therapeutic cardiac cells.

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The Role of Structural Extracellular Matrix Proteins in Urothelial Bladder Cancer (Review)

Biomarker Insights ◽

10.4137/bmi.s294 ◽

2007 ◽

Vol 2 ◽

pp. BMI.S294 ◽

Cited By ~ 14

Author(s):

Andrea Brunner ◽

Alexandar Tzankov

Keyword(s):

Extracellular Matrix ◽

Cancer Cells ◽

Cell Invasion ◽

Matrix Proteins ◽

Urothelial Bladder Cancer ◽

Ecm Proteins ◽

Cancer Review ◽

Urothelial Bladder ◽

Carcinoma Of The Bladder

The extracellular matrix (ECM) plays a key role in the modulation of cancer cell invasion. In urothelial carcinoma of the bladder (UC) the role of ECM proteins has been widely studied. The mechanisms, which are involved in the development of invasion, progression and generalization, are complex, depending on the interaction of ECM proteins with each other as well as with cancer cells. The following review will focus on the pathogenetic role and prognostic value of structural proteins, such as laminins, collagens, fibronectin (FN), tenascin (Tn-C) and thrombospondin 1 (TSP1) in UC. In addition the role of integrins mediating the interaction of ECM molecules and cancer cells will be addressed, since integrin-mediated FN, Tn-C and TSP1 interactions seem to play an important role during tumor cell invasion and angiogenesis.

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Nanoengineering in Cardiac Regeneration: Looking Back and Going Forward

Nanomaterials ◽

10.3390/nano10081587 ◽

2020 ◽

Vol 10 (8) ◽

pp. 1587

Author(s):

Caterina Cristallini ◽

Emanuela Vitale ◽

Claudia Giachino ◽

Raffaella Rastaldo

Keyword(s):

Tissue Engineering ◽

Experimental Study ◽

Extracellular Matrix ◽

Regenerative Medicine ◽

Cardiac Tissue ◽

Cardiac Regeneration ◽

Cardiac Cells ◽

Integration Process ◽

Specific Interest ◽

Looking Back

To deliver on the promise of cardiac regeneration, an integration process between an emerging field, nanomedicine, and a more consolidated one, tissue engineering, has begun. Our work aims at summarizing some of the most relevant prevailing cases of nanotechnological approaches applied to tissue engineering with a specific interest in cardiac regenerative medicine, as well as delineating some of the most compelling forthcoming orientations. Specifically, this review starts with a brief statement on the relevant clinical need, and then debates how nanotechnology can be combined with tissue engineering in the scope of mimicking a complex tissue like the myocardium and its natural extracellular matrix (ECM). The interaction of relevant stem, precursor, and differentiated cardiac cells with nanoengineered scaffolds is thoroughly presented. Another correspondingly relevant area of experimental study enclosing both nanotechnology and cardiac regeneration, e.g., nanoparticle applications in cardiac tissue engineering, is also discussed.

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Regulation of Myocardial Extracellular Matrix Dynamic Changes in Myocardial Infarction and Postinfarct Remodeling

Current Cardiology Reviews ◽

10.2174/1573403x15666190509090832 ◽

2020 ◽

Vol 16 (1) ◽

pp. 11-24 ◽

Cited By ~ 1

Author(s):

Alexey Ushakov ◽

Vera Ivanchenko ◽

Alina Gagarina

Keyword(s):

Myocardial Infarction ◽

Extracellular Matrix ◽

Transforming Growth Factor ◽

Clinical Manifestations ◽

Pivotal Role ◽

Matrix Remodeling ◽

Matricellular Proteins ◽

Myocardial Repair ◽

Cellular Mechanisms

The article represents literature review dedicated to molecular and cellular mechanisms underlying clinical manifestations and outcomes of acute myocardial infarction. Extracellular matrix adaptive changes are described in detail as one of the most important factors contributing to healing of damaged myocardium and post-infarction cardiac remodeling. Extracellular matrix is reviewed as dynamic constantly remodeling structure that plays a pivotal role in myocardial repair. The role of matrix metalloproteinases and their tissue inhibitors in fragmentation and degradation of extracellular matrix as well as in myocardium healing is discussed. This review provides current information about fibroblasts activity, the role of growth factors, particularly transforming growth factor β and cardiotrophin-1, colony-stimulating factors, adipokines and gastrointestinal hormones, various matricellular proteins. In conclusion considering the fact that dynamic transformation of extracellular matrix after myocardial ischemic damage plays a pivotal role in myocardial infarction outcomes and prognosis, we suggest a high importance of further investigation of mechanisms underlying extracellular matrix remodeling and cell-matrix interactions in cardiovascular diseases.

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Long Polar Fimbriae of Enterohemorrhagic Escherichia coli O157:H7 Bind to Extracellular Matrix Proteins

Infection and Immunity ◽

10.1128/iai.05317-11 ◽

2011 ◽

Vol 79 (9) ◽

pp. 3744-3750 ◽

Cited By ~ 38

Author(s):

Mauricio J. Farfan ◽

Lidia Cantero ◽

Roberto Vidal ◽

Douglas J. Botkin ◽

Alfredo G. Torres

Keyword(s):

Escherichia Coli ◽

Extracellular Matrix ◽

Enterohemorrhagic Escherichia Coli ◽

Matrix Proteins ◽

Intestinal Cells ◽

T84 Cells ◽

Content Type ◽

Fimbrial Subunit ◽

Ecm Proteins

ABSTRACTAdherence to intestinal cells is a key process in infection caused by enterohemorrhagicEscherichia coli(EHEC). Several adhesion factors that mediate the binding of EHEC to intestinal cells have been described, but the receptors involved in their recognition are not fully characterized. Extracellular matrix (ECM) proteins might act as receptors involved in the recognition of enteric pathogens, including EHEC. In this study, we sought to characterize the binding of EHEC O157:H7 to ECM proteins commonly present in the intestine. We found that EHEC prototype strains as well as other clinical isolates adhered more abundantly to surfaces coated with fibronectin, laminin, and collagen IV. Further characterization of this phenotype, by using antiserum raised against the LpfA1 putative major fimbrial subunit and by addition of mannose, showed that a reduced binding of EHEC to ECM proteins was observed in a long polar fimbria (lpf) mutant. We also found that the two regulators, H-NS and Ler, had an effect in EHEC Lpf-mediated binding to ECM, supporting the roles of these tightly regulated fimbriae as adherence factors. Purified Lpf major subunit bound to all of the ECM proteins tested. Finally, increased bacterial adherence was observed when T84 cells, preincubated with ECM proteins, were infected with EHEC. Taken together, these findings suggest that the interaction of Lpf and ECM proteins contributes to the EHEC colonization of the gastrointestinal tract.

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miRNA in cardiac development and regeneration

Cell Regeneration ◽

10.1186/s13619-021-00077-5 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Zhaohui Ouyang ◽

Ke Wei

Keyword(s):

Myocardial Infarction ◽

Cardiac Development ◽

Heart Function ◽

Cardiac Regeneration ◽

Biological Processes ◽

Cardiomyocyte Proliferation ◽

Delivery Methods ◽

New Strategy ◽

Improve Heart Function ◽

Multiple Species

AbstractIschemic heart disease is one of the main causes of morbidity and mortality in the world. In adult mammalian hearts, most cardiomyocytes are terminally differentiated and have extremely limited capacity of proliferation, making it impossible to regenerate the heart after injuries such as myocardial infarction. MicroRNAs (miRNAs), a class of non-coding single-stranded RNA, which are involved in mRNA silencing and the regulation of post-transcriptional gene expression, have been shown to play a crucial role in cardiac development and cardiomyocyte proliferation. Muscle specific miRNAs such as miR-1 are key regulators of cardiomyocyte maturation and growth, while miR-199-3p and other miRNAs display potent activity to induce proliferation of cardiomyocytes. Given their small size and relative pleiotropic effects, miRNAs have gained significant attraction as promising therapeutic targets or tools in cardiac regeneration. Increasing number of studies demonstrated that overexpression or inhibition of specific miRNAs could induce cardiomyocyte proliferation and cardiac regeneration. Some common targets of pro-proliferation miRNAs, such as the Hippo-Yap signaling pathway, were identified in multiple species, highlighting the power of miRNAs as probes to dissect core regulators of biological processes. A number of miRNAs have been shown to improve heart function after myocardial infarction in mice, and one trial in swine also demonstrated promising outcomes. However, technical difficulties, especially in delivery methods, and adverse effects, such as uncontrolled proliferation, remain. In this review, we summarize the recent progress in miRNA research in cardiac development and regeneration, examine the mechanisms of miRNA regulating cardiomyocyte proliferation, and discuss its potential as a new strategy for cardiac regeneration therapy.

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Domain organizations of extracellular matrix proteins and their evolution

Development ◽

10.1242/dev.1994.supplement.35 ◽

1994 ◽

Vol 1994 (Supplement) ◽

pp. 35-42

Author(s):

Jürgen Engel ◽

Vladimir P. Efimov ◽

Patrik Maurer

Keyword(s):

Extracellular Matrix ◽

Cell Signalling ◽

Coiled Coil ◽

Structure And Function ◽

Matrix Proteins ◽

Cell Binding ◽

Ecm Proteins ◽

Triple Helices ◽

And Function ◽

Polypeptide Chains

The astonishing diversity in structure and function of extracellular matrix (ECM) proteins originates from different combinations of domains. These are defined as autonomously folding units. Many domains are similar in sequence and structure indicating common ancestry. Evolutionarily homologous domains are, however, often functionally very different, which renders function prediction from sequence difficult. Related and different domains are frequently repeated in the same or in different polypeptide chains. Common assembly domains include α-helical coiled-coil domains and collagen triple helices. Other domains have been shown to be involved in assembly to other ECM proteins or in cell binding and cell signalling. The function of most of the domains, however, remains to be elucidated. ECM proteins are rather recent `inventions', and most occur either in plants or mammals but not in both. Their creation by domain shuffling involved a number of different mechanisms at the DNA level in which introns played an important role.

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Therapeutic effect of a novel Wnt pathway inhibitor on cardiac regeneration after myocardial infarction

Clinical Science ◽

10.1042/cs20171256 ◽

2017 ◽

Vol 131 (24) ◽

pp. 2919-2932 ◽

Cited By ~ 18

Author(s):

Dezhong Yang ◽

Wenbin Fu ◽

Liangpeng Li ◽

Xuewei Xia ◽

Qiao Liao ◽

...

Keyword(s):

Myocardial Infarction ◽

Cell Cycle ◽

Cardiac Function ◽

Infarct Size ◽

Cardiac Regeneration ◽

Border Zone ◽

Cardiomyocyte Proliferation ◽

Great Loss ◽

Wnt Proteins ◽

Phosphohistone H3

After myocardial infarction (MI), the heart is difficult to repair because of great loss of cardiomyoctyes and lack of cardiac regeneration. Novel drug candidates that aim at reducing pathological remodeling and stimulating cardiac regeneration are highly desirable. In the present study, we identified if and how a novel porcupine inhibitor CGX1321 influenced MI and cardiac regeneration. Permanent ligation of left anterior descending (LAD) coronary artery was performed in mice to induce MI injury. Cardiac function was measured by echocardiography, infarct size was examined by TTC staining. Fibrosis was evaluated with Masson’s trichrome staining and vimentin staining. As a result, CGX1321 administration blocked the secretion of Wnt proteins, and inhibited both canonical and non-canonical Wnt signaling pathways. CGX1321 improved cardiac function, reduced myocardial infarct size, and fibrosis of post-MI hearts. CGX1321 significantly increased newly formed cardiomyocytes in infarct border zone of post-MI hearts, evidenced by the increased EdU+ cardiomyocytes. Meanwhile, CGX1321 increased Ki67+ and phosphohistone H3 (PH3+) cardiomyocytes in culture, indicating enhanced cardiomyocyte proliferation. The mRNA microarray showed that CGX1321 up-regulated cell cycle regulating genes such as Ccnb1 and Ccne1. CGX1321 did not alter YAP protein phosphorylation and nuclear translocation in cardiomyocytes. In conclusion, porcupine inhibitor CGX1321 reduces MI injury by limiting fibrosis and promoting regeneration. It promotes cardiomyocyte proliferation by stimulating cell cycle regulating genes with a Hippo/YAP-independent pathway.

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Prediction of Extracellular Matrix Proteins by Fusing Multiple Feature Information, Elastic Net, and Random Forest Algorithm

Mathematics ◽

10.3390/math8020169 ◽

2020 ◽

Vol 8 (2) ◽

pp. 169 ◽

Cited By ~ 6

Author(s):

Minghui Wang ◽

Lingling Yue ◽

Xiaowen Cui ◽

Cheng Chen ◽

Hongyan Zhou ◽

...

Keyword(s):

Extracellular Matrix ◽

Random Forest ◽

Class Imbalance ◽

Extracellular Matrix Proteins ◽

Elastic Net ◽

Matrix Proteins ◽

Local Descriptor ◽

Ecm Proteins ◽

Multiple Feature ◽

Leave One Out

Extracellular matrix (ECM) proteins play an important role in a series of biological processes of cells. The study of ECM proteins is helpful to further comprehend their biological functions. We propose ECMP-RF (extracellular matrix proteins prediction by random forest) to predict ECM proteins. Firstly, the features of the protein sequence are extracted by combining encoding based on grouped weight, pseudo amino-acid composition, pseudo position-specific scoring matrix, a local descriptor, and an autocorrelation descriptor. Secondly, the synthetic minority oversampling technique (SMOTE) algorithm is employed to process the class imbalance data, and the elastic net (EN) is used to reduce the dimension of the feature vectors. Finally, the random forest (RF) classifier is used to predict the ECM proteins. Leave-one-out cross-validation shows that the balanced accuracy of the training and testing datasets is 97.3% and 97.9%, respectively. Compared with other state-of-the-art methods, ECMP-RF is significantly better than other predictors.

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Epicardial therapy with atrial appendage micrografts salvages myocardium after infarction

10.1101/712778 ◽

2019 ◽

Author(s):

Xie Yanbo ◽

Milla Lampinen ◽

Juuso Takala ◽

Vilbert Sikorski ◽

Rabah Soliymani ◽

...

Keyword(s):

Myocardial Infarction ◽

Extracellular Matrix ◽

Cardiac Tissue ◽

Artery Bypass ◽

Cardiac Regeneration ◽

Atrial Appendage ◽

Mortality And Morbidity ◽

The Matrix ◽

Clinical Benefits ◽

Matrix Patch

AbstractIschemic heart disease remains the leading cause of mortality and morbidity worldwide despite improved possibilities in medical care. Alongside interventional therapies, such as coronary artery bypass grafting, adjuvant tissue-engineered and cell-based treatments can provide regenerative improvement. Unfortunately, most of these advanced approaches require multiple lengthy and costly preparation stages without delivering significant clinical benefits.We evaluated the effect of epicardially delivered minute pieces of atrial appendage tissue material, defined as atrial appendage micrografts (AAMs), in mouse myocardial infarction model. An extracellular matrix patch was used to cover and fix the AAMs onto the surface of the infarcted heart. The matrix-covered AAMs salvaged the heart from infarction-induced loss of functional myocardium and attenuated scarring. Site-selective proteomics of injured ischemic and uninjured distal myocardium from AAM-treated and untreated tissue sections revealed an increased expression of several cardiac regeneration-associated proteins (i.e. periostin, transglutaminases and glutathione peroxidases) as well as activation of pathways responsible for angio- and cardiogenesis in relation to AAMs therapy.Epicardial delivery of AAMs encased in an extracellular matrix patch scaffold salvages functional cardiac tissue from ischemic injury and restricts fibrosis after myocardial infarction. Our results support the use of AAMs as tissue-based therapy adjuvants for salvaging the ischemic myocardium.

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ECMPride: prediction of human extracellular matrix proteins based on the ideal dataset using hybrid features with domain evidence

PeerJ ◽

10.7717/peerj.9066 ◽

2020 ◽

Vol 8 ◽

pp. e9066 ◽

Cited By ~ 1

Author(s):

Binghui Liu ◽

Ling Leng ◽

Xuer Sun ◽

Yunfang Wang ◽

Jie Ma ◽

...

Keyword(s):

Extracellular Matrix ◽

Large Scale ◽

Protein Identification ◽

Protein Domain ◽

Matrix Proteins ◽

Reference Database ◽

Hybrid Features ◽

Ecm Proteins ◽

Machine Learning Model ◽

Multicellular Organisms

Extracellular matrix (ECM) proteins play an essential role in various biological processes in multicellular organisms, and their abnormal regulation can lead to many diseases. For large-scale ECM protein identification, especially through proteomic-based techniques, a theoretical reference database of ECM proteins is required. In this study, based on the experimentally verified ECM datasets and by the integration of protein domain features and a machine learning model, we developed ECMPride, a flexible and scalable tool for predicting ECM proteins. ECMPride achieved excellent performance in predicting ECM proteins, with appropriate balanced accuracy and sensitivity, and the performance of ECMPride was shown to be superior to the previously developed tool. A new theoretical dataset of human ECM components was also established by applying ECMPride to all human entries in the SwissProt database, containing a significant number of putative ECM proteins as well as the abundant biological annotations. This dataset might serve as a valuable reference resource for ECM protein identification.

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