Myocardial remodeling after infarction: the role of myofibroblasts

Borne, Susanne W.M. van den; Dı́ez, Javier; Blankesteijn, W. Matthijs; Verjans, Johan; Hofstra, Leo; Narula, Jagat

doi:10.1038/nrcardio.2009.199

Cited by 633 publications

(518 citation statements)

References 69 publications

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“…30,31 This suggests that NHLFs will be more contractile and more likely to deposit ECM proteins than HCFs. [32][33][34] Our scratch-wound assay revealed that the NHLFs cultured on the lung ECM migrate faster than the HCFs cultured on cardiac ECM, which agrees with the higher expression of aSMA seen in NHLFs. In addition to this increased motility, NHLFs exhibited a higher percentage of proliferating cells when compared to HCFs.…”

Section: Discussionsupporting

confidence: 69%

Differential β₃Integrin Expression Regulates the Response of Human Lung and Cardiac Fibroblasts to Extracellular Matrix and Its Components

Merna

Fung

Wang

et al. 2015

Tissue Engineering Part A

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Extracellular matrix (ECM) derived from whole organ decellularization has been successfully used in a variety of tissue engineering applications. ECM contains a complex mixture of functional and structural molecules that are ideally suited for the tissue from which the ECM is harvested. However, decellularization disrupts the structural properties and protein composition of the ECM, which may impact function when cells such as the fibroblast are reintroduced during recellularization. We hypothesized that the ECM structure and composition, fibroblast source, and integrin expression would influence the fibroblast phenotype. Human cardiac fibroblasts (HCFs) and normal human lung fibroblasts (NHLFs) were cultured on intact cardiac ECM, collagen gels, and coatings composed of cardiac ECM, lung ECM, and individual ECM components (collagen and fibronectin [FN]) for 48 h. COL1A expression of HCFs and NHLFs cultured on ECM and FN coatings decreased to <50% of that of untreated cells; COL1A expression for HCFs cultured on ECM coatings was one-to twofold higher than HCFs cultured on intact ECM. NHLFs cultured on ECM and FN coatings expressed 12-to 31-fold more alpha-smooth muscle actin (aSMA) than HCFs; the aSMA expression for HCFs and NHLFs cultured on ECM coatings was *2-to 5-fold higher than HCFs and NHLFs cultured on intact ECM. HCFs expressed significantly higher levels of b 3 and b 4 integrins when compared to NHLFs. Inhibition of the b 3 integrin, but not b 4 , resulted in a 16-to 26-fold increase in aSMA expression in HCFs cultured on ECM coatings and FN. Our results demonstrate that b 3 integrin expression depends on the source of the fibroblast and that its expression inhibits aSMA expression (and thus the myofibroblast phenotype). We conclude that the fibroblast source and integrin expression play important roles in regulating the fibroblast phenotype.

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Section: Discussionsupporting

confidence: 69%

Differential β₃Integrin Expression Regulates the Response of Human Lung and Cardiac Fibroblasts to Extracellular Matrix and Its Components

Merna

Fung

Wang

et al. 2015

Tissue Engineering Part A

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“…Second, there may be a need for cells to rapidly shift position in response to ongoing structural changes and mechanical forces, a circumstance highly relevant to the remodeling infarct zone. 36 We found that in hearts expressing collagenase-resistant collagen there was reduced alignment of myofibroblasts entering the infarct zone. Because fibroblast/myofibroblast alignment defines collagen fibril alignment, this impaired ability to reorient could be an additional means by which the fidelity of scar formation was reduced.…”

Section: Discussionmentioning

confidence: 83%

“…In vivo, cleavage of recently deposited collagen may also be relevant, particularly because collagen deposition and maturation during wound healing can proceed over days to weeks. 20,36 The ability of fibroblasts to quickly reorient and finetune their direction of traveling within remodeling tissue could serve two purposes. First, it could ensure that the cell can explore and test its new environment efficiently.…”

Section: Discussionmentioning

confidence: 99%

Type I Collagen Cleavage Is Essential for Effective Fibrotic Repair after Myocardial Infarction

Zhang

O’Neil

Lei

et al. 2011

The American Journal of Pathology

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Efficient deposition of type I collagen is fundamental to healing after myocardial infarction. Whether there is also a role for cleavage of type I collagen in infarct healing is unknown. To test this, we undertook coronary artery occlusion in mice with a targeted mutation (Col1a1 r/r ) that yields collagenase-resistant type I collagen. Eleven days after infarction, Col1a1 r/r mice had a lower mean arterial pressure and peak left ventricular systolic pressure, reduced ventricular systolic function, and worse diastolic function, compared with wild-type littermates. Infarcted Col1a1 r/r mice also had greater 30-day mortality, larger left ventricular lumens, and thinner infarct walls. Interestingly, the collagen fibril content within infarcts of mutant mice was not increased. However, circular polarization microscopy revealed impaired collagen fibril organization and mechanical testing indicated a predisposition to scar microdisruption. Three-dimensional lattices of collagenase-resistant fibrils underwent cell-mediated contraction, but the fibrils did not organize into birefringent collagen bundles. In addition, time-lapse microscopy revealed that, although cells migrated smoothly on wild-type collagen fibrils, crawling and repositioning on collagenase-resistant collagen was impaired. We conclude that type I collagen cleavage is required for efficient healing of myocardial infarcts and is critical for both dynamic positioning of collagen-producing cells and hierarchical assembly of collagen fibrils. This seemingly paradoxical requirement for collagen cleavage in fibrotic repair should be considered when designing potential strategies to inhibit matrix degradation in cardiac disease. Rapid deposition of type I collagen is critical to cardiac repair after myocardial infarction. When effectively elaborated, a type I collagen-rich matrix provides a mechanically strong network that maintains cardiac integrity, minimizes infarct expansion, and resists maladaptive remodeling.1 Elaboration of type I collagen is a multistep process that includes expression of the genes encoding pro-␣1(I) and pro-␣2(I) collagen chains, intracellular winding of the chains, and secretion of type I procollagen. Outside the cell, the propeptide termini are cleaved and the resulting triple helical type I collagen assembles into fibrils, which then cross-link and pack. Collagen deposition can be opposed by processes that degrade type I collagen. Enzymes that destroy the integrity of type I collagen by cleaving the triple helical domain are important in this regard. These include the interstitial collagenases, matrix metalloproteinase (MMP)Ϫ1, MMP-8, and MMP-13, that cleave type I collagen three fourths along the length of its triple helix. Broader-spectrum MMPs, such as MMP-2 and membrane-type (MT)1-MMP/MMP-14, also have the capacity to cleave native type I collagen.3,4 Several studies have highlighted the potential for interstitial collagenases to adversely affect the heart. Transgenic expression of MMP-1 promotes ventricular dilatation and dysfun...

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“…chemokines and cytokines that facilitate recruitment and activation of inflammatory cells in the damaged area of the heart [1][2][3][4][5][6]9].…”

mentioning

confidence: 99%

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

Turner

2016

Journal of Molecular and Cellular Cardiology

166

124

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Cardiac fibroblasts (CF) are well-established as key regulators of extracellular matrix (ECM) turnover in the context of myocardial remodelling and fibrosis. Recently, this cell type has also been shown to act as a sensor of myocardial damage by detecting and responding to damage-associated molecular patterns (DAMPs) upregulated with cardiac injury. CF express a range of innate immunity pattern recognition receptors (TLRs, NLRs, IL-1R1, RAGE) that are stimulated by a host of different DAMPs that are evident in the injured or remodelling myocardium. These include intracellular molecules released by necrotic cells (heat shock proteins, high mobility group box 1 protein, S100 proteins), proinflammatory cytokines (interleukin-1), specific ECM molecules up-regulated in response to tissue injury (fibronectin-EDA, tenascin-C) or molecules modified by a pathological environment (advanced glycation end product-modified proteins observed with diabetes). DAMP receptor activation on fibroblasts is coupled to altered cellular function including changes in proliferation, migration, myofibroblast transdifferentiation, ECM turnover and production of fibrotic and inflammatory paracrine factors, which directly impact on the heart's ability to respond to injury. This review gives an overview of the important role played by CF in responding to myocardial DAMPs and how the DAMP/CF axis could be exploited experimentally and therapeutically.3

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Myocardial remodeling after infarction: the role of myofibroblasts

Abstract: Background: The mechanisms involved in the biggest remodeling caused by the post-infarct beta-carotene are unknown.

Cited by 633 publications

References 69 publications

Differential β₃Integrin Expression Regulates the Response of Human Lung and Cardiac Fibroblasts to Extracellular Matrix and Its Components

Differential β₃Integrin Expression Regulates the Response of Human Lung and Cardiac Fibroblasts to Extracellular Matrix and Its Components

Type I Collagen Cleavage Is Essential for Effective Fibrotic Repair after Myocardial Infarction

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

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Myocardial remodeling after infarction: the role of myofibroblasts

Abstract: Background: The mechanisms involved in the biggest remodeling caused by the post-infarct beta-carotene are unknown.

Cited by 633 publications

References 69 publications

Differential β3Integrin Expression Regulates the Response of Human Lung and Cardiac Fibroblasts to Extracellular Matrix and Its Components

Differential β3Integrin Expression Regulates the Response of Human Lung and Cardiac Fibroblasts to Extracellular Matrix and Its Components

Type I Collagen Cleavage Is Essential for Effective Fibrotic Repair after Myocardial Infarction

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

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Product

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Differential β₃Integrin Expression Regulates the Response of Human Lung and Cardiac Fibroblasts to Extracellular Matrix and Its Components

Differential β₃Integrin Expression Regulates the Response of Human Lung and Cardiac Fibroblasts to Extracellular Matrix and Its Components