Reprogramming cardiomyocyte mechanosensing by crosstalk between integrins and hyaluronic acid receptors

Department of Biomedical Engineering, Drexel University, Philadelphia, PA 19102, USA.
Journal of Biomechanics (Impact Factor: 2.5). 12/2011; 45(5):824-31. DOI: 10.1016/j.jbiomech.2011.11.023
Source: PubMed

ABSTRACT The elastic modulus of bioengineered materials has a strong influence on the phenotype of many cells including cardiomyocytes. On polyacrylamide (PAA) gels that are laminated with ligands for integrins, cardiac myocytes develop well organized sarcomeres only when cultured on substrates with elastic moduli in the range 10 kPa-30 kPa, near those of the healthy tissue. On stiffer substrates (>60 kPa) approximating the damaged heart, myocytes form stress fiber-like filament bundles but lack organized sarcomeres or an elongated shape. On soft (<1 kPa) PAA gels myocytes exhibit disorganized actin networks and sarcomeres. However, when the polyacrylamide matrix is replaced by hyaluronic acid (HA) as the gel network to which integrin ligands are attached, robust development of functional neonatal rat ventricular myocytes occurs on gels with elastic moduli of 200 Pa, a stiffness far below that of the neonatal heart and on which myocytes would be amorphous and dysfunctional when cultured on polyacrylamide-based gels. The HA matrix by itself is not adhesive for myocytes, and the myocyte phenotype depends on the type of integrin ligand that is incorporated within the HA gel, with fibronectin, gelatin, or fibrinogen being more effective than collagen I. These results show that HA alters the integrin-dependent stiffness response of cells in vitro and suggests that expression of HA within the extracellular matrix (ECM) in vivo might similarly alter the response of cells that bind the ECM through integrins. The integration of HA with integrin-specific ECM signaling proteins provides a rationale for engineering a new class of soft hybrid hydrogels that can be used in therapeutic strategies to reverse the remodeling of the injured myocardium.

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    • "Interestingly , there is a matrix-dependent response of CMs to substrate stiffness. Hyaluronic acid (HA) has the potential to alter CMs' integrin-mediated response to stiffness, because when cultured on extremely soft substrates in the presence of HA, CMs maintain their ability to form organized sarcomeres [43]. Further work is needed to understand the mechanism by which substrate composition mediates the cellular response to stiffness. "
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    • "Rather than that, cells kept a round shaped morphology and did not interconnect to build up a contracting tissue construct. This was not surprising, since alginate and hyaluronic acid display low cell-adhesiveness [59] [60], which might also interfere with cell migration and tissue formation. Nevertheless , Live/Dead stainings demonstrated excellent cell viability within hydrogels, which highlights the value of this system for potential approaches like cell/hydrogel injection or tissue engineering of constructs with low cell density like cartilage and bone. "
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Anant Chopra