Engineering Extracellular Matrix Proteins to Enhance Cardiac Regeneration After Myocardial Infarction.
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ABSTRACT:
SUBMITTER: Esmaeili H
PROVIDER: S-EPMC7855456 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundOptimal healing of the myocardium following myocardial infarction (MI) requires a suitable degree of inflammation and its timely resolution, together with a well-orchestrated deposition and degradation of extracellular matrix (ECM) proteins.Methods and resultsMI and SHAM-operated animals were imaged at 3,7,14 and 21 days with 3T magnetic resonance imaging (MRI) using a 19F/1H surface coil. Mice were injected with 19F-perfluorocarbon (PFC) nanoparticles to study inflammatory cell recruitment, and with a gadolinium-based elastin-binding contrast agent (Gd-ESMA) to evaluate elastin content. 19F MRI signal co-localized with infarction areas, as confirmed by late-gadolinium enhancement, and was highest 7days post-MI, correlating with macrophage content (MAC-3 immunohistochemistry) (ρ=0.89,P<0.0001). 19F quantification with in vivo (MRI) and ex vivo nuclear magnetic resonance (NMR) spectroscopy correlated linearly (ρ=0.58,P=0.020). T1 mapping after Gd-ESMA injection showed increased relaxation rate (R1) in the infarcted regions and was significantly higher at 21days compared with 7days post-MI (R1[s-1]:21days=2.8 [IQR,2.69-3.30] vs 7days=2.3 [IQR,2.12-2.5], P<0.05), which agreed with an increased tropoelastin content (ρ=0.89, P<0.0001). The predictive value of each contrast agent for beneficial remodeling was evaluated in a longitudinal proof-of-principle study. Neither R1 nor 19F at day 7 were significant predictors for beneficial remodeling (P=0.68;P=0.062). However, the combination of both measurements (R1<2.34Hz and 0.55≤19F≤1.85) resulted in an odds ratio of 30.0 (CI95%:1.41-638.15;P=0.029) for favorable post-MI remodeling.ConclusionsMultinuclear 1H/19F MRI allows the simultaneous assessment of inflammation and elastin remodeling in a murine MI model. The interplay of these biological processes affects cardiac outcome and may have potential for improved diagnosis and personalized treatment.
| S-EPMC6277008 | biostudies-literature
Project description:Clinical studies have demonstrated the regenerative potential of stem cells for cardiac repair over the past decades, but their widespread use is limited by the poor tissue integration and survival obtained. Natural or synthetic hydrogels or microcarriers, used as cell carriers, contribute to resolving, in part, the problems encountered by providing mechanical support for the cells allowing cell retention, survival and tissue integration. Moreover, hydrogels alone also possess mechanical protective properties for the ischemic heart. The combined effect of growth factors with cells and an appropriate scaffold allow a therapeutic effect on myocardial repair. Despite this, the effects obtained with cell therapy remain limited and seem to be equivalent to the effects obtained with extracellular vesicles, key actors in intercellular communication. Extracellular vesicles have cardioprotective effects which, when combined proangiogenic properties with antiapoptotic and anti-inflammatory actions, make it possible to act on all the damages caused by ischemia. The evolution of biomaterial engineering allows us to envisage their association with new major players in cardiac therapy, extracellular vesicles, in order to limit undesirable effects and to envisage a transfer to the clinic. This new therapeutic approach could be associated with the release of growth factors to potentialized the beneficial effect obtained.
| S-EPMC7763019 | biostudies-literature
Project description:IntroductionThe prevalence of heart failure increases in the aging population and following myocardial infarction (MI), yet the extracellular matrix (ECM) remodeling underpinning the development of aging- and MI-associated cardiac fibrosis remains poorly understood. A link between inflammation and fibrosis in the heart has long been appreciated, but has mechanistically remained undefined. We investigated the expression of a novel protein, extracellular matrix protein 1 (ECM1) in the aging and infarcted heart.MethodsYoung adult (3-month old) and aging (18-month old) C57BL/6 mice were assessed. Young mice were subjected to left anterior descending artery-ligation to induce MI, or transverse aortic constriction (TAC) surgery to induce pressure-overload cardiomyopathy. Left ventricle (LV) tissue was collected early and late post-MI/TAC. Bone marrow cells (BMCs) were isolated from young healthy mice, and subject to flow cytometry. Human cardiac fibroblast (CFb), myocyte, and coronary artery endothelial & smooth muscle cell lines were cultured; human CFbs were treated with recombinant ECM1. Primary mouse CFbs were cultured and treated with recombinant angiotensin-II or TGF-β1. Immunoblotting, qPCR and mRNA fluorescent in-situ hybridization (mRNA-FISH) were conducted on LV tissue and cells.ResultsECM1 expression was upregulated in the aging LV, and in the infarct zone of the LV early post-MI. No significant differences in ECM1 expression were found late post-MI or at any time-point post-TAC. ECM1 was not expressed in any resident cardiac cells, but ECM1 was highly expressed in BMCs, with high ECM1 expression in granulocytes. Flow cytometry of bone marrow revealed ECM1 expression in large granular leucocytes. mRNA-FISH revealed that ECM1 was indeed expressed by inflammatory cells in the infarct zone at day-3 post-MI. ECM1 stimulation of CFbs induced ERK1/2 and AKT activation and collagen-I expression, suggesting a pro-fibrotic role.ConclusionsECM1 expression is increased in ageing and infarcted hearts but is not expressed by resident cardiac cells. Instead it is expressed by bone marrow-derived granulocytes. ECM1 is sufficient to induce cardiac fibroblast stimulation in vitro. Our findings suggest ECM1 is released from infiltrating inflammatory cells, which leads to cardiac fibroblast stimulation and fibrosis in aging and MI. ECM1 may be a novel intermediary between inflammation and fibrosis.
| S-EPMC6383988 | biostudies-literature
Project description:The myocardial extracellular matrix (ECM), an interwoven meshwork of proteins, glycoproteins, proteoglycans, and glycosaminoglycans that is dominated by polymeric fibrils of type I collagen, serves as the mechanical scaffold on which myocytes are arrayed for coordinated and synergistic force transduction. Following ischemic injury, cardiac ECM remodeling is initiated via localized proteolysis, the bulk of which has been assigned to matrix metalloproteinase (MMP) family members. Nevertheless, the key effector(s) of myocardial type I collagenolysis both in vitro and in vivo have remained unidentified. In this study, using cardiac explants from mice deficient in each of the major type I collagenolytic MMPs, including MMP-13, MMP-8, MMP-2, MMP-9, or MT1-MMP, we identify the membrane-anchored MMP, MT1-MMP, as the dominant collagenase that is operative within myocardial tissues in vitro. Extending these observations to an in vivo setting, mice heterozygous for an MT1-MMP-null allele display a distinct survival advantage and retain myocardial function relative to wild-type littermates in an experimental model of myocardial infarction, effects associated with preservation of the myocardial type I collagen network as a consequence of the decreased collagenolytic potential of cardiac fibroblasts. This study identifies MT1-MMP as a key MMP responsible for effecting postinfarction cardiac ECM remodeling and cardiac dysfunction.
| S-EPMC3349831 | biostudies-other
Project description:Researchers continue to develop therapeutic products for the repair and replacement of myocardial tissue that demonstrates contractility equivalent to normal physiologic states. As clinical trials focused on pure adult stem cell populations undergo meta-analysis for preclinical through clinical design, the field of tissue engineering is emerging as a new clinical frontier to repair the myocardium and improve cardiac output. This review will first discuss the three primary tissue engineering product themes that are advancing in preclinical to clinical models: (1) cell-free scaffolds, (2) scaffold-free cellular, and (3) hybrid cell and scaffold products. The review will then focus on the products that have advanced from preclinical models to clinical trials. In advancing the cardiac regenerative medicine field, long-term gains towards discovering an optimal product to generate functional myocardial tissue and eliminate heart failure may be achieved.
| S-EPMC7305042 | biostudies-literature
Project description:We have previously shown that MicroRNA (miR) -144 is a key modulator of the acute cardioprotection associated with remote ischemic preconditioning and post myocardial infarction (MI) remodeling. In this study we examine the biology of the remodeling response after permanent ligation of the left anterior descending coronary artery in male miR-144 KO mice, and wild-type littermates (WT). Collagen content and cross linking were determined by hydroxyproline and pyridinoline assays, MI size and scar thickness were measured post PicoSirius Red staining, and cardiac function was evaluated by echocardiography. miR-144 KO mice developed normally with normal cardiac function, however after MI, infarction size was greater and scar thickness was reduced in miR-144 KO mice compared with WT littermates. miR-144 KO mice had a lower incidence of acute cardiac rupture compared with WT littermates early after MI but there was impaired late remodeling, reflected by increased total cardiac collagen content and collagen cross-linkage associated with changes in Zeb1/LOX1 axis, and decreased left ventricular ejection fraction. We conclude that miR-144 is involved in extracellular matrix remodeling post MI and its loss leads to increased myocardial fibrosis and impaired functional recovery.
| S-EPMC6237773 | biostudies-literature
Project description:This study evaluated the safety and feasibility of transendocardial injections of VentriGel, a cardiac extracellular matrix hydrogel, in early and late post-myocardial infarction (MI) patients with left ventricular (LV) dysfunction. VentriGel was delivered in 15 patients with moderate LV dysfunction (25% ≤ LV ejection fraction ≤ 45%) who were between 60 days to 3 years post-MI and were revascularized by percutaneous coronary intervention. The primary endpoints were incidence of adverse events and abnormal clinical laboratory results. This first-in-man study established the safety and feasibility of delivering VentriGel in post-MI patients, thus warranting further evaluation in larger, randomized clinical trials.
| S-EPMC6834965 | biostudies-literature
Project description:Decellularized extracellular matrix (dECM) is a promising biomaterial for repairing cardiovascular tissue, as dECM most effectively captures the complex array of proteins, glycosaminoglycans, proteoglycans, and many other matrix components that are found in native tissue, providing ideal cues for regeneration and repair of damaged myocardium. dECM can be used in a variety of forms, such as solid scaffolds that maintain native matrix structure, or as soluble materials that can form injectable hydrogels for tissue repair. dECM has found recent success in many regeneration and repair therapies, such as for musculoskeletal, neural, and liver tissues. This review focuses on dECM in the context of cardiovascular applications, with variations in tissue and species sourcing, and specifically discusses advances in solid and soluble dECM development, in vitro studies, in vivo implementation, and clinical translation.
| S-EPMC7654553 | biostudies-literature
Project description:Heart attack is a global health problem that leads to significant morbidity, mortality, and health care burden. Adult human hearts have very limited regenerative capability after injury. However, evolutionarily primitive species generally have higher regenerative capacity than mammals. The extracellular matrix (ECM) may contribute to this difference. Mammalian cardiac ECM may not be optimally inductive for cardiac regeneration because of the fibrotic, instead of regenerative, responses in injured adult mammalian hearts. Given the high regenerative capacity of adult zebrafish hearts, we hypothesize that decellularized zebrafish cardiac ECM (zECM) made from normal or healing hearts can induce mammalian heart regeneration. Using zebrafish and mice as representative species of lower vertebrates and mammals, we show that a single administration of zECM, particularly the healing variety, enables cardiac functional recovery and regeneration of adult mouse heart tissues after acute myocardial infarction. zECM-treated groups exhibit proliferation of the remaining cardiomyocytes and multiple cardiac precursor cell populations and reactivation of ErbB2 expression in cardiomyocytes. Furthermore, zECM exhibits pro-proliferative and chemotactic effects on human cardiac precursor cell populations in vitro. These contribute to the structural preservation and correlate with significantly higher cardiac contractile function, notably less left ventricular dilatation, and substantially more elastic myocardium in zECM-treated hearts than control animals treated with saline or decellularized adult mouse cardiac ECM. Inhibition of ErbB2 activity abrogates beneficial effects of zECM administration, indicating the possible involvement of ErbB2 signaling in zECM-mediated regeneration. This study departs from conventional focuses on mammalian ECM and introduces a new approach for cardiac tissue regeneration.
| S-EPMC5262469 | biostudies-literature
Project description:Heart failure is a progressive deterioration of cardiac pump function over time and is often a manifestation of ischemic injury caused by myocardial infarction (MI). Post-MI, structural remodeling of the infarcted myocardium ensues. Dysregulation of extracellular matrix (ECM) homeostasis is a hallmark of structural cardiac remodeling and is largely driven by cardiac fibroblast activation. While initially adaptive, structural cardiac remodeling leads to irreversible heart failure due to the progressive loss of cardiac function. Loss of pump function is associated with myocardial fibrosis, wall thinning, and left ventricular (LV) dilatation. Surgical revascularization of the damaged myocardium via coronary artery bypass graft (CABG) surgery and/or percutaneous coronary intervention (PCI) can enhance myocardial perfusion and is beneficial. However, these interventions alone are unable to prevent progressive fibrotic remodeling and loss of heart function that leads to clinical end-stage heart failure. Acellular biologic ECM scaffolds can be surgically implanted onto injured myocardial regions during open-heart surgery as an adjunct therapy to surgical revascularization. This presents a novel therapeutic approach to alter maladaptive remodeling and promote functional recovery. Acellular ECM bioscaffolds have been shown to provide passive structural support to the damaged myocardium and also to act as a dynamic bioactive reservoir capable of promoting endogenous mechanisms of tissue repair, such as vasculogenesis. The composition and structure of xenogenic acellular ECM bioscaffolds are determined by the physiological requirements of the tissue from which they are derived. The capacity of different tissue-derived acellular bioscaffolds to attenuate cardiac remodeling and restore ECM homeostasis after injury may depend on such properties. Accordingly, the search and discovery of an optimal ECM bioscaffold for use in cardiac repair is warranted and may be facilitated by comparing bioscaffolds. This review will provide a summary of the acellular ECM bioscaffolds currently available for use in cardiac surgery with a focus on how they attenuate cardiac remodeling by providing the necessary environmental cues to promote endogenous mechanisms of tissue repair.
| S-EPMC6497812 | biostudies-literature