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Research Papers

The Role of Cardiac Fibroblasts in Extracellular Matrix-Mediated Signaling During Normal and Pathological Cardiac Development

[+] Author and Article Information
Kelly Elizabeth Sullivan

Department of Biomedical Engineering,
Tufts University,
4 Colby Street,
Medford, MA 02155

Lauren Deems Black, III

Department of Biomedical Engineering,
Tufts University,
4 Colby Street,
Medford, MA 02155;
Cellular, Molecular and Developmental Biology Program,
Sackler School of Graduate Biomedical Sciences,
Tufts University School of Medicine,
145 Harrison Ave,
Boston, MA 02111
e-mail: lauren.black@tufts.edu

1Corresponding author.

Contributed by the Bioengineering Division of ASME for publication in the JOURNAL OF BIOMECHANICAL ENGINEERING. Manuscript received December 14, 2012; final manuscript received April 24, 2013; accepted manuscript posted April 30, 2013; published online June 11, 2013. Assoc. Editor: Keith Gooch.

J Biomech Eng 135(7), 071001 (Jun 11, 2013) (9 pages) Paper No: BIO-12-1618; doi: 10.1115/1.4024349 History: Received December 14, 2012; Revised April 24, 2013; Accepted April 30, 2013

The extracellular matrix is no longer considered a static support structure for cells but a dynamic signaling network with the power to influence cell, tissue, and whole organ physiology. In the myocardium, cardiac fibroblasts are the primary cell type responsible for the synthesis, deposition, and degradation of matrix proteins, and they therefore play a critical role in the development and maintenance of functional heart tissue. This review will summarize the extensive research conducted in vivo and in vitro, demonstrating the influence of both physical and chemical stimuli on cardiac fibroblasts and how these interactions impact both the extracellular matrix and, by extension, cardiomyocytes. This work is of considerable significance, given that cardiovascular diseases are marked by extensive remodeling of the extracellular matrix, which ultimately impairs the functional capacity of the heart. We seek to summarize the unique role of cardiac fibroblasts in normal cardiac development and the most prevalent cardiac pathologies, including congenital heart defects, hypertension, hypertrophy, and the remodeled heart following myocardial infarction. We will conclude by identifying existing holes in the research that, if answered, have the potential to dramatically improve current therapeutic strategies for the repair and regeneration of damaged myocardium via mechanotransductive signaling.

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Figures

Grahic Jump Location
Fig. 1

A schematic illustrating the dynamic role of CFs during development, normal and pathological physiology of myocardia through their interactions with CMs, and the ECM. References described in detail within text.

Grahic Jump Location
Fig. 2

The CF phenotype is dynamically regulated by the physical (substrate stiffness and mechanical stimulation) and chemical mediators (substrate composition and soluble factors) present within the extracellular environment of the myocardium. (a) Migration rates of CFs are dependent on matrix density [18]. (b) Mechanotransductive ion channels regulate CF differentiation to a myofibroblast phenotype through the integration of physical stimulation (substrate stiffness) and chemical mediators (TGF-β1) [32]. (c) Matrix production is enhanced following mechanical stretch and dependent on substrate composition [21]. (d) Periostin mRNA expression is significantly upregulated in the presence of IL-18 [47].

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