The extracellular matrix in myocardial injury, repair, and remodeling
01 May 2017-Journal of Clinical Investigation (American Society for Clinical Investigation)-Vol. 127, Iss: 5, pp 1600-1612
TL;DR: The role of the ECM in cardiac repair and remodeling is reviewed and matrix-based therapies that may attenuate remodeling while promoting repair and regeneration are discussed.
Abstract: The cardiac extracellular matrix (ECM) not only provides mechanical support, but also transduces essential molecular signals in health and disease. Following myocardial infarction, dynamic ECM changes drive inflammation and repair. Early generation of bioactive matrix fragments activates proinflammatory signaling. The formation of a highly plastic provisional matrix facilitates leukocyte infiltration and activates infarct myofibroblasts. Deposition of matricellular proteins modulates growth factor signaling and contributes to the spatial and temporal regulation of the reparative response. Mechanical stress due to pressure and volume overload and metabolic dysfunction also induce profound changes in ECM composition that contribute to the pathogenesis of heart failure. This manuscript reviews the role of the ECM in cardiac repair and remodeling and discusses matrix-based therapies that may attenuate remodeling while promoting repair and regeneration.
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TL;DR: Development of effective therapies will require careful dissection of the cell biological mechanisms, study of the functional consequences of fibrotic changes on the myocardium, and identification of heart failure patient subsets with overactive fibrotics responses.
455 citations
TL;DR: These same lineage-traced initial fibroblasts persisted within the scar, achieving a new molecular and stable differentiated state referred to as a matrifibrocyte, which was also observed in the scars of human hearts.
Abstract: Fibroblasts are a dynamic cell type that achieve selective differentiated states to mediate acute wound healing and long-term tissue remodeling with scarring. With myocardial infarction injury, cardiomyocytes are replaced by secreted extracellular matrix proteins produced by proliferating and differentiating fibroblasts. Here, we employed 3 different mouse lineage-tracing models and stage-specific gene profiling to phenotypically analyze and classify resident cardiac fibroblast dynamics during myocardial infarction injury and stable scar formation. Fibroblasts were activated and highly proliferative, reaching a maximum rate within 2 to 4 days after infarction injury, at which point they expanded 3.5-fold and were maintained long term. By 3 to 7 days, these cells differentiated into myofibroblasts that secreted abundant extracellular matrix proteins and expressed smooth muscle α-actin to structurally support the necrotic area. By 7 to 10 days, myofibroblasts lost proliferative ability and smooth muscle α-actin expression as the collagen-containing extracellular matrix and scar fully matured. However, these same lineage-traced initial fibroblasts persisted within the scar, achieving a new molecular and stable differentiated state referred to as a matrifibrocyte, which was also observed in the scars of human hearts. These cells express common and unique extracellular matrix and tendon genes that are more specialized to support the mature scar.
393 citations
Cites background from "The extracellular matrix in myocard..."
...Once induced, myofibroblasts produce and secrete greater levels of ECM proteins, including multiple types of collagen, and they express contractile genes, such as smooth muscle α-actin (αSMA), that underlie their ability to contract and close a wounded area (7, 8)....
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TL;DR: The role of ECM macromolecules in heart failure is discussed, focusing on both structural ECM proteins (such as fibrillar and nonfibrilar collagens), and specialized injury-associated matrix macromolescules ( such as fibronectin and matricellular proteins).
Abstract: The ECM (extracellular matrix) network plays a crucial role in cardiac homeostasis, not only by providing structural support, but also by facilitating force transmission, and by transducing key sig...
270 citations
TL;DR: This review presents an overview of what is known about cardiac fibrosis including the role of cardiac cells and extracellular matrix in this disease, and summarizes current diagnostic tools and highlights pre-clinical or clinical therapeutic strategies to address this disease.
232 citations
TL;DR: Understanding the comprehensive molecules and pathways involved in ECM homeostasis and remodeling may provide important novel potential targets for preventing and treating cardiac fibrosis.
198 citations
References
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TL;DR: This work has identified endostatin, an angiogenesis inhibitor produced by hemangioendothelioma, a 20 kDa C-terminal fragment of collagen XVIII that specifically inhibits endothelial proliferation and potently inhibitsAngiogenesis and tumor growth.
4,613 citations
"The extracellular matrix in myocard..." refers background in this paper
...Endostatin, a 20-kDa fragment of collagen XVIII, exerts potent angiostatic actions (45) and stimulates fibroblast proliferation (46)....
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TL;DR: It is clear that the understanding of the myofibroblast — its origins, functions and molecular regulation — will have a profound influence on the future effectiveness not only of tissue engineering but also of regenerative medicine generally.
Abstract: During the past 20 years, it has become generally accepted that the modulation of fibroblastic cells towards the myofibroblastic phenotype, with acquisition of specialized contractile features, is essential for connective-tissue remodelling during normal and pathological wound healing. Yet the myofibroblast still remains one of the most enigmatic of cells, not least owing to its transient appearance in association with connective-tissue injury and to the difficulties in establishing its role in the production of tissue contracture. It is clear that our understanding of the myofibroblast its origins, functions and molecular regulation will have a profound influence on the future effectiveness not only of tissue engineering but also of regenerative medicine generally.
3,836 citations
TL;DR: The capacity to generate cardiomyocytes in the adult human heart suggests that it may be rational to work toward the development of therapeutic strategies aimed at stimulating this process in cardiac pathologies.
Abstract: It has been difficult to establish whether we are limited to the heart muscle cells we are born with or if cardiomyocytes are generated also later in life. We have taken advantage of the integration of carbon-14, generated by nuclear bomb tests during the Cold War, into DNA to establish the age of cardiomyocytes in humans. We report that cardiomyocytes renew, with a gradual decrease from 1% turning over annually at the age of 25 to 0.45% at the age of 75. Fewer than 50% of cardiomyocytes are exchanged during a normal life span. The capacity to generate cardiomyocytes in the adult human heart suggests that it may be rational to work toward the development of therapeutic strategies aimed at stimulating this process in cardiac pathologies.
2,804 citations
TL;DR: Eight constructs decellularized hearts by coronary perfusion with detergents, preserved the underlying extracellular matrix, and produced an acellular, perfusable vascular architecture, competent a cellular valves and intact chamber geometry that could generate pump function in a modified working heart preparation.
Abstract: About 3,000 individuals in the United States are awaiting a donor heart; worldwide, 22 million individuals are living with heart failure. A bioartificial heart is a theoretical alternative to transplantation or mechanical left ventricular support. Generating a bioartificial heart requires engineering of cardiac architecture, appropriate cellular constituents and pump function. We decellularized hearts by coronary perfusion with detergents, preserved the underlying extracellular matrix, and produced an acellular, perfusable vascular architecture, competent acellular valves and intact chamber geometry. To mimic cardiac cell composition, we reseeded these constructs with cardiac or endothelial cells. To establish function, we maintained eight constructs for up to 28 d by coronary perfusion in a bioreactor that simulated cardiac physiology. By day 4, we observed macroscopic contractions. By day 8, under physiological load and electrical stimulation, constructs could generate pump function (equivalent to about 2% of adult or 25% of 16-week fetal heart function) in a modified working heart preparation.
2,454 citations
"The extracellular matrix in myocard..." refers background in this paper
...A growing body of experimental work attempts to exploit technological advances in perfusion-decellularization strategies (152) to generate scaffolds comprising human cardiac ECM that may serve as tools for manufacture of cardiac grafts (153, 154)....
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TL;DR: It is shown that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart.
Abstract: Cardiac fibrosis, associated with a decreased extent of microvasculature and with disruption of normal myocardial structures, results from excessive deposition of extracellular matrix, which is mediated by the recruitment of fibroblasts. The source of these fibroblasts is unclear and specific anti-fibrotic therapies are not currently available. Here we show that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart. Transforming growth factor-β1 (TGF-β1) induced endothelial cells to undergo EndMT, whereas bone morphogenic protein 7 (BMP-7) preserved the endothelial phenotype. The systemic administration of recombinant human BMP-7 (rhBMP-7) significantly inhibited EndMT and the progression of cardiac fibrosis in mouse models of pressure overload and chronic allograft rejection. Our findings show that EndMT contributes to the progression of cardiac fibrosis and that rhBMP-7 can be used to inhibit EndMT and to intervene in the progression of chronic heart disease associated with fibrosis.
1,908 citations