Reprogramming cardiomyocyte mechanosensing by crosstalk between integrins and hyaluronic acid receptors

Chopra, Anant; Lin, Victor; McCollough, Amanda; Atzet, Sarah; Prestwich, Glenn D.; Wechsler, Andrew S.; Murray, Maria E.; Oake, Shaina A.; Yasha Kresh, J.; Janmey, Paul A.

doi:10.1016/j.jbiomech.2011.11.023

« Previous Next »Journal of Biomechanics
Volume 45, Issue 5 , Pages 824-831, 15 March 2012

Reprogramming cardiomyocyte mechanosensing by crosstalk between integrins and hyaluronic acid receptors

Anant Chopra
- Department of Biomedical Engineering, Drexel University, Philadelphia, PA, USA
Victor Lin
- Department of Cardiothoracic Surgery, Drexel University College of Med, Philadelphia, PA, USA
Amanda McCollough
- Glycosan Biosystems, Salt Lake City, UT, USA
Sarah Atzet
- Glycosan Biosystems, Salt Lake City, UT, USA
Glenn D. Prestwich
- Glycosan Biosystems, Salt Lake City, UT, USA
Andrew S. Wechsler
- Department of Cardiothoracic Surgery, Drexel University College of Med, Philadelphia, PA, USA
Maria E. Murray
- Institute for Medicine and Engineering, University of Pennsylvania, 1010 Vagelos Laboratories, 3340 Smith Walk, Philadelphia, PA 19104, USA
Shaina A. Oake
- Institute for Medicine and Engineering, University of Pennsylvania, 1010 Vagelos Laboratories, 3340 Smith Walk, Philadelphia, PA 19104, USA
J. Yasha Kresh
- Department of Biomedical Engineering, Drexel University, Philadelphia, PA, USA
- Department of Cardiothoracic Surgery, Drexel University College of Med, Philadelphia, PA, USA
- Corresponding author at: Department of Cardiothoracic Surgery, Drexel University College of Medicine, 245 N 15th Street, PA 19102, USA. Tel.: +215 762 1703.
Paul A. Janmey
- Institute for Medicine and Engineering, University of Pennsylvania, 1010 Vagelos Laboratories, 3340 Smith Walk, Philadelphia, PA 19104, USA
- Corresponding author. Tel.: +215 573 7380; fax: +215 573 6815.

Accepted 4 October 2011. published online 26 December 2011.

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 10kPa–30kPa, near those of the healthy tissue. On stiffer substrates (>60kPa) approximating the damaged heart, myocytes form stress fiber-like filament bundles but lack organized sarcomeres or an elongated shape. On soft (<1kPa) 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 200Pa, 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.