The extracellular matrix: at the center of it all.

Texas A&M Health Science Center College of Medicine, Division of Molecular Cardiology, 1901 South 1st Street, Building 205, Room 1R24, Temple, TX 76504, USA.
Journal of Molecular and Cellular Cardiology (Impact Factor: 5.15). 09/2009; 48(3):474-82. DOI: 10.1016/j.yjmcc.2009.08.024
Source: PubMed

ABSTRACT The extracellular matrix is not only a scaffold that provides support for cells, but it is also involved in cell-cell interactions, proliferation and migration. The intricate relationships among the cellular and acellular components of the heart drive proper heart development, homeostasis and recovery following pathological injury. Cardiac myocytes, fibroblasts and endothelial cells differentially express and respond to particular extracellular matrix factors that contribute to cell communication and overall cardiac function. In addition, turnover and synthesis of ECM components play an important role in cardiac function. Therefore, a better understanding of these factors and their regulation would lend insight into cardiac development and pathology, and would open doors to novel targeted pharmacologic therapies. This review highlights the importance of contributions of particular cardiac cell populations and extracellular matrix factors that are critical to the development and regulation of heart function.

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    ABSTRACT: Cardiomyocytes (CMs) derived from human pluripotent stem cells (hPSCs) offer immense value in studying cardiovascular regenerative medicine. However, intrinsic biases and differential responsiveness of hPSCs towards cardiac differentiation pose significant technical and logistic hurdles that hamper human cardiomyocyte studies. Tandem modulation of canonical and non-canonical Wnt Signaling pathways may play a crucial role in cardiac development that can efficiently generate cardiomyocytes from pluripotent stem cells. Our Wnt signaling expression profiles revealed that phasic modulation of canonical/non-canonical axis enabled orderly recapitulation of cardiac developmental ontogeny. Moreover, evaluation of 8 hPSC lines showed marked commitment towards cardiac-mesoderm during the early phase of differentiation, with elevated levels of canonical Wnts (Wnt3 and 3a) and Mesp1. Whereas continued activation of canonical Wnts was counterproductive, its discrete inhibition during the later phase of cardiac differentiation was accompanied by significant up-regulation of non-canonical Wnt expression (Wnt5a and 11) and enhanced Nkx2.5(+) (up to 98%) populations. These Nkx2.5(+) populations transited to contracting cardiac troponin T-positive CMs with up to 80% efficiency. Our results suggest that timely modulation of Wnt pathways would transcend intrinsic differentiation biases of hPSCs to consistently generate functional CMs that could facilitate their scalable production for meaningful clinical translation towards personalized regenerative medicine.
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 11/2014; 1843(11):2394–2402. · 5.30 Impact Factor
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    ABSTRACT: Living tissue is composed of cells and extracellular matrix (ECM). In the heart and blood vessels, which are constantly subjected to mechanical stress, ECM molecules form well-developed fibrous frameworks to maintain tissue structure. ECM is also important for biological signaling, which influences various cellular functions in embryonic development, and physiological/pathological responses to extrinsic stimuli. Among ECM molecules, increased attention has been focused on matricellular proteins. Matricellular proteins are a growing group of non-structural ECM proteins highly up-regulated at active tissue remodeling, serving as biological mediators. Tenascin-C (TNC) is a typical matricellular protein, which is highly expressed during embryonic development, wound healing, inflammation, and cancer invasion. The expression is tightly regulated, dependent on the microenvironment, including various growth factors, cytokines, and mechanical stress. In the heart, TNC appears in a spatiotemporal-restricted manner during early stages of development, sparsely detected in normal adults, but transiently re-expressed at restricted sites associated with tissue injury and inflammation. Similarly, in the vascular system, TNC is strongly up-regulated during embryonic development and under pathological conditions with an increase in hemodynamic stress. Despite its intriguing expression pattern, cardiovascular system develops normally in TNC knockout mice. However, deletion of TNC causes acute aortic dissection (AAD) under strong mechanical and humoral stress. Accumulating reports suggest that TNC may modulate the inflammatory response and contribute to elasticity of the tissue, so that it may protect cardiovascular tissue from destructive stress responses. TNC may be a key molecule to control cellular activity during development, adaptation, or pathological tissue remodeling.
    Frontiers in Physiology 07/2014; 5:283.
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    ABSTRACT: Early in embryogenesis, the heart begins its rhythmic contractions as a tube that helps perfuse the nascent vasculature, but the embryonic heart soon changes shape and mechanical properties, like many other developing organs. A key question in the field is whether stresses in development impact the underlying gene circuits and, if so, how? Here, we attempt to address this question as we review the mechanical maturation of heart - and, to a limited extent, lung and blood - with a focus on a few key abundant structural proteins whose expression dynamics have been suggested to be directly sensitive to mechanical stress. In heart maturation, proliferating fibroblasts deposit increasing amounts of collagenous matrix in parallel with cardiomyocytes expressing more sarcomeric proteins that increase the contractile stress and strength of the tissue, which in turn pumps more blood at higher stress throughout the developing vasculature. Feedback of beating cardiomyocytes on the expression of matrix by fibroblasts seems a reasonable model, with both synthesis and turnover of matrix and contractile elements achieving a suitable balance. Based on emerging evidence for coiled-coil biopolymers that are tension-stabilized against degradation, a minimal network model of a dynamic cell-matrix interaction is proposed. This same concept is extended to nuclear mechanics as regulated by stress on the nuclear structural proteins called lamins, which are examined in part because of the prominence of mutations in these coiled-coil proteins in diseases of the heart, amongst other organs/tissues. Variations in lamin levels during development and across adult tissues are to some extent known and appear to correlate with extracellular matrix mechanics, which we illustrate across heart, lung, and blood development. The formal perspective here on the mechanochemistry of tissue development and homeostasis could provide a useful framework for 'big data' quantitative biology, particularly of stress-sensitive differentiation, maturation, and disease processes.
    Current biology : CB. 05/2014; 24(10):R495-R501.

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