The interaction between valve cells and their microenvironment signals determine the functional output of cardiac valve tissues; cardiac valve diseases might be caused by a disruption of these interactions
In vitro cell culture studies can help understand cardiac valve disease pathobiology, which is enhanced by culturing cells on biomaterials that mimic the native valve cell matrix environment
Many biochemical signals regulate pathogenic phenotypes of cells in the valve; however, their effects are dependent on the matrix microenvironment
Synthetic biomaterials can be used to understand valve cell regulation by biochemical, biophysical, and other matrix-associated signals, especially related to the development of valvular diseases
Understanding the dynamic interplay between microenvironmental signals and valvular cell phenotypes will enable the identification of new therapies and the design of ex vivo tissue engineered valves
During every heartbeat, cardiac valves open and close coordinately to control the unidirectional flow of blood. In this dynamically challenging environment, resident valve cells actively maintain homeostasis, but the signalling between cells and their microenvironment is complex. When homeostasis is disrupted and the valve opening obstructed, haemodynamic profiles can be altered and lead to impaired cardiac function. Currently, late stages of cardiac valve diseases are treated surgically, because no drug therapies exist to reverse or halt disease progression. Consequently, investigators have sought to understand the molecular and cellular mechanisms of valvular diseases using in vitro cell culture systems and biomaterial scaffolds that can mimic the extracellular microenvironment. In this Review, we describe how signals in the extracellular matrix regulate valve cell function. We propose that the cellular context is a critical factor when studying the molecular basis of valvular diseases in vitro, and one should consider how the surrounding matrix might influence cell signalling and functional outcomes in the valve. Investigators need to build a systems-level understanding of the complex signalling network involved in valve regulation, to facilitate drug target identification and promote in situ or ex vivo heart valve regeneration.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Schoen, F. J. Evolving concepts of cardiac valve dynamics. Circulation 118, 1864–1880 (2008).
Balachandran, K., Sucosky, P. & Yoganathan, A. P. Hemodynamics and mechanobiology of aortic valve inflammation and calcification. Int. J. Inflam. 2011, 263870 (2011).
Gould, S. T., Srigunapalan, S., Simmons, C. A. & Anseth, K. S. Hemodynamic and cellular response feedback in calcific aortic valve disease. Circ. Res. 113, 186–197 (2013).
Hinton, R. & Yutzey, K. E. Heart valve structure and function in development and disease. Annu. Rev. Physiol. 73, 29–46 (2011).
Vesely, I. The role of elastin in aortic valve mechanics. J. Biomech. 31, 115–123 (1998).
Bischoff, J. & Aikawa, E. Progenitor cells confer plasticity to cardiac valve endothelium. J. Cardiovasc. Transl. Res. 4, 710–719 (2011).
Rajamannan, N. M. et al. Calcific aortic valve disease: not simply a degenerative process. Circulation 124, 1783–1791 (2011).
Rabkin, E. et al. Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves. Circulation 104, 2525–2532 (2001).
Levine, R. A. & Schwammenthal, E. Ischemic mitral regurgitation on the threshold of a solution: from paradoxes to unifying concepts. Circulation 112, 745–758 (2005).
Armstrong, E. J. & Bischoff, J. Heart valve development: endothelial cell signaling and differentiation. Circ. Res. 95, 459–470 (2004).
Combs, M. D. & Yutzey, K. E. Heart valve development: regulatory networks in development and disease. Circ. Res. 105, 408–421 (2009).
Roger, V. L. et al. Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation 123, e18–e209 (2011).
Gharacholou, S. M., Karon, B. L., Shub, C. & Pellikka, P. A. Aortic valve sclerosis and clinical outcomes: moving toward a definition. Am. J. Med. 124, 103–110 (2011).
Freeman, R. V. & Otto, C. M. Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies. Circulation 111, 3316–3326 (2005).
Otto, C. M., Lind, B. K., Kitzman, D. W., Gersh, B. J. & Siscovick, D. S. Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly. N. Engl. J. Med. 341, 142–147 (1999).
Bonow, R. O. et al. 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 guidelines for the management of patients with valvular heart disease) endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J. Am. Coll. Cardiol. 52, e1–e142 (2008).
Hutcheson, J. D., Aikawa, E. & Merryman, W. D. Potential drug targets for calcific aortic valve disease. Nat. Rev. Cardiol. 11, 218–231 (2014).
Guy, T. S. & Hill, A. C. Mitral valve prolapse. Annu. Rev. Med. 63, 277–292 (2012).
Miller, J. D., Weiss, R. M. & Heistad, D. D. Calcific aortic valve stenosis: methods, models, and mechanisms. Circ. Res. 108, 1392–1412 (2011).
Weiss, R. M., Miller, J. D. & Heistad, D. D. Fibrocalcific aortic valve disease: opportunity to understand disease mechanisms using mouse models. Circ. Res. 113, 209–222 (2013).
Sider, K. L., Blaser, M. C. & Simmons, C. A. Animal models of calcific aortic valve disease. Int. J. Inflam. 2011, 18 (2011).
Rajamannan, N. M. et al. Human aortic valve calcification is associated with an osteoblast phenotype. Circulation 107, 2181–2184 (2003).
Sainger, R. et al. Human myxomatous mitral valve prolapse: role of bone morphogenetic protein 4 in valvular interstitial cell activation. J. Cell Physiol. 227, 2595–2604 (2012).
Santos, E., Orive, G., Hernández, R. M. & Pedraz, J. L. Cell-Biomaterial interaction: strategies to mimic the extracellular matrix [online], (2011).
Liu, A. C., Joag, V. R. & Gotlieb, A. I. The emerging role of valve interstitial cell phenotypes in regulating heart valve pathobiology. Am. J. Pathol. 171, 1407–1418 (2007).
Leopold, J. A. Cellular mechanisms of aortic valve calcification. Circ. Cardiovasc. Interv. 5, 605–614 (2012).
Bertazzo, S. et al. Nano-analytical electron microscopy reveals fundamental insights into human cardiovascular tissue calcification. Nat. Mater. 12, 576–583 (2013).
Pohle, K. et al. Progression of aortic valve calcification: association with coronary atherosclerosis and cardiovascular risk factors. Circulation 104, 1927–1932 (2001).
Cowell, S. J. et al. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N. Engl. J. Med. 352, 2389–2397 (2005).
Walker, G. A., Masters, K. S., Shah, D. N., Anseth, K. S. & Leinwand, L. A. Valvular myofibroblast activation by transforming growth factor-beta1. Circ. Res. 95, 253–260 (2004).
Paranya, G. et al. Aortic valve endothelial cells undergo transforming growth factor-beta-mediated and non-transforming growth factor-beta-mediated transdifferentiation in vitro. Am. J. Pathol. 159, 1335–1343 (2001).
Pho, M. et al. Cofilin is a marker of myofibroblast differentiation in cells from porcine aortic cardiac valves. Am. J. Physiol. Heart Circ. Physiol. 294, H1767–H1778 (2008).
Egan, K. P., Kim, J.-H., Mohler, E. R. & Pignolo, R. J. Role for circulating osteogenic precursor cells in aortic valvular disease. Arterioscler. Thromb. Vasc. Biol. 31, 2965–2971 (2011).
Gossl, M. et al. Role of circulating osteogenic progenitor cells in calcific aortic stenosis. J. Am. Coll. Cardiol. 60, 1945–1953 (2012).
Gooch, J. L., Gorin, Y., Zhang, B.-X. & Abboud, H. E. Involvement of calcineurin in transforming growth factor-beta-mediated regulation of extracellular matrix accumulation. J. Biol. Chem. 279, 15561–15570 (2004).
Kagami, S., Border, W. A., Miller, D. E. & Noble, N. A. Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells. J. Clin. Invest. 93, 2431–2437 (1994).
Hinz, B. The myofibroblast: paradigm for a mechanically active cell. J. Biomech. 43, 146–155 (2010).
Tomasek, J. J., Gabbiani, G., Hinz, B., Chaponnier, C. & Brown, R. A. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell Biol. 3, 349–363 (2002).
Henderson, N. C. & Iredale, J. P. Liver fibrosis: cellular mechanisms of progression and resolution. Clin. Sci. (Lond.) 112, 265–280 (2007).
King, T. E., Pardo, A. & Selman, M. Idiopathic pulmonary fibrosis. Lancet 378, 1949–1961 (2011).
Liu, Y. Cellular and molecular mechanisms of renal fibrosis. Nat. Rev. Nephrol. 7, 684–696 (2011).
Santiago, J.-J. et al. Cardiac fibroblast to myofibroblast differentiation in vivo and in vitro: Expression of focal adhesion components in neonatal and adult rat ventricular myofibroblasts. Dev. Dyn. 239, 1573–1584 (2010).
Hinz, B. et al. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am. J. Pathol. 180, 1340–1355 (2012).
Wynn, T. A. & Ramalingam, T. R. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat. Med. 18, 1028–1040 (2012).
Desmoulière, A., Redard, M., Darby, I. & Gabbiani, G. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am. J. Pathol. 146, 56–66 (1995).
Grinnell, F., Zhu, M., Carlson, M. A. & Abrams, J. M. Release of mechanical tension triggers apoptosis of human fibroblasts in a model of regressing granulation tissue. Exp. Cell Res. 248, 608–619 (1999).
Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008).
Kisseleva, T. et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc. Natl Acad. Sci. USA 109, 9448–9453 (2012).
Wang, H., Haeger, S. M., Kloxin, A. M., Leinwand, L. A. & Anseth, K. S. Redirecting valvular myofibroblasts into dormant fibroblasts through light-mediated reduction in substrate modulus. PLoS ONE 7, e39969 (2012).
Monzack, E. L. & Masters, K. S. Can valvular interstitial cells become true osteoblasts? A side-by-side comparison. J. Heart Valve Dis. 20, 449–463 (2011).
Cloyd, K. L. et al. Characterization of porcine aortic valvular interstitial cell 'calcified' nodules. PLoS ONE 7, e48154 (2012).
Alexopoulos, A. et al. Bone regulatory factors NFATc1 and Osterix in human calcific aortic valves. Int. J. Cardiol. 139, 142–149 (2010).
Miller, J. D. et al. Evidence for active regulation of pro-osteogenic signaling in advanced aortic valve disease. Arterioscler. Thromb. Vasc. Biol. 30, 2482–2486 (2010).
Yang, X. et al. Bone morphogenic protein 2 induces Runx2 and osteopontin expression in human aortic valve interstitial cells: role of Smad1 and extracellular signal-regulated kinase 1/2. J. Thorac. Cardiovasc. Surg. 138, 1008–1015 (2009).
Balachandran, K., Sucosky, P., Jo, H. & Yoganathan, A. P. Elevated cyclic stretch induces aortic valve calcification in a bone morphogenic protein-dependent manner. Am. J. Pathol. 177, 49–57 (2010).
Mohler, E., Gannon, F., Reynolds, C., Zimmerman, R., Keane, M. G., Kaplan, F. S. Bone formation and inflammation in cardiac valves. Circulation 103, 1522–1528 (2001).
Yip, C. Y. Y., Chen, J.-H., Zhao, R. & Simmons, C. A. Calcification by valve interstitial cells is regulated by the stiffness of the extracellular matrix. Arterioscler. Thromb. Vasc. Biol. 29, 936–942 (2009).
Chen, J.-H., Yip, C. Y. Y., Sone, E. D. & Simmons, C. A. Identification and characterization of aortic valve mesenchymal progenitor cells with robust osteogenic calcification potential. Am. J. Pathol. 174, 1109–1119 (2009).
Jian, B., Narula, N., Li, Q.-y., Mohler, E. R. III & Levy, R. J. Progression of aortic valve stenosis: TGF-β1 is present in calcified aortic valve cusps and promotes aortic valve interstitial cell calcification via apoptosis. Ann. Thorac. Surg. 75, 457–465 (2003).
Wang, H., Sridhar, B., Leinwand, L. A. & Anseth, K. S. Characterization of cell subpopulations expressing progenitor cell markers in porcine cardiac valves. PLoS ONE 8, e69667 (2013).
Benton, J., Kern, H. B., Leinwand, L. A., Mariner, P. D., Anseth, K. S. Statins block calcific nodule formation of valvular interstitial cells by inhibiting alpha-smooth muscle actin expression. Arterioscler. Thromb. Vasc. Biol. 29, 1950–1957 (2009).
Rajamannan, N. M. et al. Calcified rheumatic valve neoangiogenesis is associated with vascular endothelial growth factor expression and osteoblast-like bone formation. Circulation 111, 3296–3301 (2005).
Caira, F. C. et al. Human degenerative valve disease is associated with up-regulation of low-density lipoprotein receptor-related protein 5 receptor-mediated bone formation. J. Am. Coll. Cardiol 47, 1707–1712 (2006).
Mahler, G. J., Farrar, E. J. & Butcher, J. T. Inflammatory cytokines promote mesenchymal transformation in embryonic and adult valve endothelial cells. Arterioscler. Thromb. Vasc. Biol. 33, 121–130 (2013).
Sewell-Loftin, M. K. et al. Myocardial contraction and hyaluronic acid mechanotransduction in epithelial-to-mesenchymal transformation of endocardial cells. Biomaterials 35, 2809–2815 (2014).
Paruchuri, S. et al. Human pulmonary valve progenitor cells exhibit endothelial/mesenchymal plasticity in response to vascular endothelial growth factor-a and transforming growth factor-β2. Circ. Res. 99, 861–869 (2006).
Kaden, J. J. et al. Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis. Atherosclerosis 170, 205–211 (2003).
Kaden, J. J. et al. Tumor necrosis factor alpha promotes an osteoblast-like phenotype in human aortic valve myofibroblasts: a potential regulatory mechanism of valvular calcification. Int. J. Mol. Med. 16, 869–872 (2005).
Nadlonek, N. et al. Interleukin-1 Beta induces an inflammatory phenotype in human aortic valve interstitial cells through nuclear factor kappa Beta. Ann. Thorac. Surg. 96, 155–162 (2013).
Sunami, Y. et al. Hepatic activation of IKK/NFkappaB signaling induces liver fibrosis via macrophage-mediated chronic inflammation. Hepatology 56, 1117–1128 (2012).
Bodas, M. & Vij, N. The NF-kappaB signaling in cystic fibrosis lung disease: pathophysiology and therapeutic potential. Discov. Med. 9, 346–356 (2010).
Stephan, M. T., Moon, J. J., Um, S. H., Bershteyn, A. & Irvine, D. J. Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nat. Med. 16, 1035–1041 (2010).
Butcher, J. T. & Nerem, R. M. Valvular endothelial cells and the mechanoregulation of valvular pathology. Phil. Trans. R. Soc. B Biol. Sci. 362, 1445–1457 (2007).
Richards, J. et al. Side-specific endothelial-dependent regulation of aortic valve calcification: interplay of hemodynamics and nitric oxide signaling. Am. J. Pathol. 182, 1922–1931 (2013).
Gould, S. T., Matherly, E. E., Smith, J. N., Heistad, D. D. & Anseth, K. S. The role of valvular endothelial cell paracrine signaling and matrix elasticity on valvular interstitial cell activation. Biomaterials 35, 3596–3606 (2014).
Yip, C. Y., Blaser, M. C., Mirzaei, Z., Zhong, X. & Simmons, C. A. Inhibition of pathological differentiation of valvular interstitial cells by c-type natriuretic peptide. Arterioscler. Thromb. Vasc. Biol. 31, 1881–1889 (2011).
Chester, A. H. Endothelin-1 and the aortic valve. Curr. Vasc. Pharmacol. 3, 353–357 (2005).
Leask, A. & Abraham, D. J. TGF-beta signaling and the fibrotic response. FASEB J. 18, 816–827 (2004).
Clark-Greuel, J. N. et al. Transforming growth factor-beta1 mechanisms in aortic valve calcification: increased alkaline phosphatase and related events. Ann. Thorac. Surg. 83, 946–953 (2007).
Dweck, M. R., Boon, N. A. & Newby, D. E. Calcific aortic stenosis: a disease of the valve and the myocardium. J. Am. Coll. Cardiol. 60, 1854–1863 (2012).
Horowitz, J. C. et al. Combinatorial activation of FAK and AKT by transforming growth factor-beta1 confers an anoikis-resistant phenotype to myofibroblasts. Cell. Signal. 19, 761–771 (2007).
Thannickal, V. J. et al. Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. J. Biol. Chem. 278, 12384–12389 (2003).
Meyer-Ter-Vehn, T. et al. p38 Inhibitors prevent TGF-beta-induced myofibroblast transdifferentiation in human tenon fibroblasts. Invest. Ophthalmol. Vis. Sci. 47, 1500–1509 (2006).
O'Brien, K. D. et al. Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of 'degenerative' valvular aortic stenosis. Arterioscler. Thromb. Vasc. Biol. 16, 523–532 (1996).
Demer, L. L. & Tintut, Y. Inflammatory, metabolic, and genetic mechanisms of vascular calcification. Arterioscler. Thromb. Vasc. Biol. 34, 715–723 (2014).
Leask, A. Potential therapeutic targets for cardiac fibrosis: TGFβ, angiotensin, endothelin, CCN2, and PDGF, partners in fibroblast activation. Circ. Res. 106, 1675–1680 (2010).
Geirsson, A. et al. Modulation of transforming growth factor-beta signaling and extracellular matrix production in myxomatous mitral valves by angiotensin II receptor blockers. Circulation 126, S189–S197 (2012).
Miller, J. D. et al. Dysregulation of antioxidant mechanisms contributes to increased oxidative stress in calcific aortic valvular stenosis in humans. J. Am. Coll. Cardiol. 52, 843–850 (2008).
Boström, K. I., Rajamannan, N. M. & Towler, D. A. The regulation of valvular and vascular sclerosis by osteogenic morphogens. Circ. Res. 109, 564–577 (2011).
Cushing, M. C., Mariner, P. D., Liao, J.-T., Sims, E. A. & Anseth, K. S. Fibroblast growth factor represses Smad-mediated myofibroblast activation in aortic valvular interstitial cells. FASEB J. 22, 1769–1777 (2008).
Rothman, R. B. et al. Evidence for possible involvement of 5-HT2B receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation 102, 2836–2841 (2000).
Hutcheson, J. D., Ryzhova, L. M., Setola, V. & Merryman, W. D. 5-HT(2B) antagonism arrests non-canonical TGF-beta1-induced valvular myofibroblast differentiation. J. Mol. Cell. Cardiol. 53, 707–714 (2012).
Hynes, R. O. The extracellular matrix: not just pretty fibrils. Science 326, 1216–1219 (2009).
Boudreau, N. J. & Jones, P. L. Extracellular matrix and integrin signalling: the shape of things to come. Biochem. J. 339, 481–488 (1999).
Kim, S.-H., Turnbull, J. & Guimond, S. Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor. J. Endocrinol. 209, 139–151 (2011).
Schwartz, M. A. Integrins and extracellular matrix in mechanotransduction. Cold Spring Harb. Perspect. Biol. 2, 17 (2010).
Dalby, M. J., Gadegaard, N. & Oreffo, R. O. C. Harnessing nanotopography and integrin-matrix interactions to influence stem cell fate. Nat. Mater. 13, 558–569 (2014).
Gilbert, P. M. et al. Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture. Science 329, 1078–1081 (2010).
Wang, H., Tibbitt, M. W., Langer, S. J., Leinwand, L. A. & Anseth, K. S. Hydrogels preserve native phenotypes of valvular fibroblasts through an elasticity-regulated PI3K/AKT pathway. Proc. Natl Acad. Sci. USA 110, 19336–19341 (2013).
Benton, J. A., Kern, H. B. & Anseth, K. S. Substrate properties influence calcification in valvular interstitial cell culture. J. Heart Valve Dis. 17, 689–699 (2008).
Baker, B. M. & Chen, C. S. Deconstructing the third dimension—how 3D culture microenvironments alter cellular cues. J. Cell Sci. 125, 3015–3024 (2012).
Wiltz, D. et al. Extracellular matrix organization, structure, and function [online], (2013).
Moraes, C. et al. Microdevice array-based identification of distinct mechanobiological response profiles in layer-specific valve interstitial cells. Integr. Biol. 5, 673–680 (2013).
Cushing, M. C., Liao, J. T. & Anseth, K. S. Activation of valvular interstitial cells is mediated by transforming growth factor-beta1 interactions with matrix molecules. Matrix Biol. 24, 428–437 (2005).
Gu, X. & Masters, K. S. Regulation of valvular interstitial cell calcification by adhesive peptide sequences. J. Biomed. Mater. Res. A 93, 1620–1630 (2010).
Chen, J.-H. & Simmons, C. A. Cell-matrix interactions in the pathobiology of calcific aortic valve disease: critical roles for matricellular, matricrine, and matrix mechanics cues. Circ. Res. 108, 1510–1524 (2011).
Gupta, V., Werdenberg, J. A., Blevins, T. L. & Grande-Allen, K. J. Synthesis of glycosaminoglycans in differently loaded regions of collagen gels seeded with valvular interstitial cells. Tissue Eng. 13, 41–49 (2007).
Butcher, J. T. & Nerem, R. M. Porcine aortic valve interstitial cells in three-dimensional culture: comparison of phenotype with aortic smooth muscle cells. J. Heart Valve Dis. 13, 478–485 (2004).
Grande-Allen, K. J. et al. Glycosaminoglycan synthesis and structure as targets for the prevention of calcific aortic valve disease. Cardiovasc. Res. 76, 19–28 (2007).
Eckert, C. E. et al. On the biomechanical role of glycosaminoglycans in the aortic heart valve leaflet. Acta Biomater. 9, 4653–4660 (2013).
Cushing, M. C., Liao, J. T., Jaeggli, M. P. & Anseth, K. S. Material-based regulation of the myofibroblast phenotype. Biomaterials 28, 3378–3387 (2007).
Rodriguez, K. J. & Masters, K. S. Regulation of valvular interstitial cell calcification by components of the extracellular matrix. J. Biomed. Mater. Res. A 90, 1043–1053 (2009).
Powell, A. K., Yates, E. A., Fernig, D. G. & Turnbull, J. E. Interactions of heparin/heparan sulfate with proteins: appraisal of structural factors and experimental approaches. Glycobiology 14, 17R–30R (2004).
Masters, K. S., Shah, D. N., Leinwand, L. A. & Anseth, K. S. Crosslinked hyaluronan scaffolds as a biologically active carrier for valvular interstitial cells. Biomaterials 26, 2517–2525 (2005).
Duan, B., Hockaday, L. A., Kapetanovic, E., Kang, K. H. & Butcher, J. T. Stiffness and adhesivity control aortic valve interstitial cell behavior within hyaluronic acid based hydrogels. Acta Biomater. 9, 7640–7650 (2013).
Shah, D. N., Recktenwall-Work, S. M. & Anseth, K. S. The effect of bioactive hydrogels on the secretion of extracellular matrix molecules by valvular interstitial cells. Biomaterials 29, 2060–2072 (2008).
Cuff, C. A. et al. The adhesion receptor CD44 promotes atherosclerosis by mediating inflammatory cell recruitment and vascular cell activation. J. Clin. Invest. 108, 1031–1040 (2001).
Misra, S., Toole, B. P. & Ghatak, S. Hyaluronan constitutively regulates activation of multiple receptor tyrosine kinases in epithelial and carcinoma cells. J. Biol. Chem. 281, 34936–34941 (2006).
Tseng, H. & Grande-Allen, K. J. Elastic fibers in the aortic valve spongiosa: a fresh perspective on its structure and role in overall tissue function. Acta Biomater. 7, 2101–2108 (2011).
Hinton, R. B. et al. Elastin haploinsufficiency results in progressive aortic valve malformation and latent valve disease in a mouse model. Circ. Res. 107, 549–557 (2010).
Hinton, R. B. et al. Extracellular matrix remodeling and organization in developing and diseased aortic valves. Circ. Res. 98, 1431–1438 (2006).
Simionescu, A., Simionescu, D. T. & Vyavahare, N. R. Osteogenic responses in fibroblasts activated by elastin degradation products and transforming growth factor-β1: role of myofibroblasts in vascular calcification. Am. J. Pathol. 171, 116–123 (2007).
Steinhoff, G. et al. Tissue engineering of pulmonary heart valves on allogenic acellular matrix conduits: in vivo restoration of valve tissue. Circulation 102 (Suppl. 3), III50–III55 (2000).
Cebotari, S. et al. Clinical application of tissue engineered human heart valves using autologous progenitor cells. Circulation 114 (Suppl.), I132–I137 (2006).
Wong, M. L. & Griffiths, L. G. Immunogenicity in xenogeneic scaffold generation: antigen removal vs. decellularization. Acta Biomater. 10, 1806–1816 (2014).
Gould, S. T., Darling, N. J. & Anseth, K. S. Small peptide functionalized thiol-ene hydrogels as culture substrates for understanding valvular interstitial cell activation and de novo tissue deposition. Acta Biomater. 8, 3201–3209 (2012).
Schmedlen, R. H., Masters, K. S. & West, J. L. Photocrosslinkable polyvinyl alcohol hydrogels that can be modified with cell adhesion peptides for use in tissue engineering. Biomaterials 23, 4325–4332 (2002).
Tibbitt, M. W. & Anseth, K. S. Hydrogels as extracellular matrix mimics for 3D cell culture. Biotechol. Bioeng. 103, 655–663 (2009).
Engler, A. J., Sen, S., Sweeney, H. L. & Discher, D. E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006).
Benton, J. A., Fairbanks, B. D. & Anseth, K. S. Characterization of valvular interstitial cell function in three dimensional matrix metalloproteinase degradable PEG hydrogels. Biomaterials 30, 6593–6603 (2009).
Gould, S. T. & Anseth, K. S. Role of cell-matrix interactions on VIC phenotype and tissue deposition in 3D PEG hydrogels. J. Tissue Eng. Regen Med. http://dx.doi.org/10.1002/term.1836.
Konitsiotis, A. D. et al. Characterization of high affinity binding motifs for the discoidin domain receptor DDR2 in collagen. J. Biol. Chem. 283, 6861–6868 (2008).
Parenteau-Bareil, R., Gauvin, R. & Berthod, F. Collagen-based biomaterials for tissue engineering applications. Materials 3, 1863–1887 (2010).
McCall, J. D., Luoma, J. E. & Anseth, K. S. Covalently tethered transforming growth factor beta in PEG hydrogels promotes chondrogenic differentiation of encapsulated human mesenchymal stem cells. Drug Deliv. Transl. Res. 2, 305–312 (2012).
Lee, K., Silva, E. A. & Mooney, D. J. Growth factor delivery-based tissue engineering: general approaches and a review of recent developments. J. R. Soc. Interface 8, 153–170 (2011).
Lutolf, M. P. et al. Repair of bone defects using synthetic mimetics of collagenous extracellular matrices. Nat. Biotechnol. 21, 513–518 (2003).
Wipff, P.-J., Rifkin, D. B., Meister, J.-J. & Hinz, B. Myofibroblast contraction activates latent TGF- beta1 from the extracellular matrix. J. Cell Biol. 179, 1311–1323 (2007).
Jenkins, G. The role of proteases in transforming growth factor-beta activation. Int. J. Biochem. Cell Biol. 40, 1068–1078 (2008).
Lin, C.-C. & Anseth, K. S. Controlling affinity binding with peptide-functionalized poly(ethylene glycol) hydrogels. Adv. Funct. Mater. 19, 2325–2331 (2009).
Callister, W. D. Fundamentals of Materials Science and Engineering: an Interactive E-Text, 5th edn 153–157 (Wiley, 2000).
Zhao, R., Sider, K. L. & Simmons, C. A. Measurement of layer-specific mechanical properties in multilayered biomaterials by micropipette aspiration. Acta Biomater. 7, 1220–1227 (2011).
Krishnamurthy, V. K., Guilak, F., Narmoneva, D. A. & Hinton, R. B. Regional structure–function relationships in mouse aortic valve tissue. J. Biomech. 44, 77–83 (2011).
Sewell-Loftin, M. K., Brown, C. B., Baldwin, H. S. & Merryman, W. D. A novel technique for quantifying mouse heart valve leaflet stiffness with atomic force microscopy. J. Heart Valve Dis. 21, 513–520 (2012).
Stella, J. A. & Sacks, M. S. On the biaxial mechanical properties of the layers of the aortic valve leaflet. J. Biomech. Eng. 129, 757–766 (2007).
Kloxin, A. M., Benton, J. A. & Anseth, K. S. In situ elasticity modulation with dynamic substrates to direct cell phenotype. Biomaterials 31, 1–8 (2010).
Liu, F. et al. Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression. J. Cell Biol. 190, 693–706 (2010).
Chen, J.-H., Chen, W. L. K., Sider, K. L., Yip, C. Y. Y. & Simmons, C. A. β-Catenin mediates mechanically regulated, transforming growth factor-β1 induced myofibroblast differentiation of aortic valve interstitial cells. Arterioscler. Thromb. Vasc. Biol. 31, 590–597 (2011).
Olsen, A. L. et al. Hepatic stellate cells require a stiff environment for myofibroblastic differentiation. Am. J. Physiol. Gastrointest. Liver Physiol. 301, G110–G118 (2011).
Wang, H.-B., Dembo, M. & Wang, Y.-L. Substrate flexibility regulates growth and apoptosis of normal but not transformed cells. Am. J. Physiol. Cell. Physiol. 279, C1345–C1350 (2000).
Zhang, Y.-H., Zhao, C.-Q., Jiang, L.-S. & Dai, L.-Y. Substrate stiffness regulates apoptosis and the mRNA expression of extracellular matrix regulatory genes in the rat annular cells. Matrix Biol. 30, 135–144 (2011).
Kural, M. H. & Billiar, K. L. Mechanoregulation of valvular interstitial cell phenotype in the third dimension. Biomaterials 35, 1128–1137 (2014).
Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).
Witt, W., Selle, A., Jannasch, A., Matschke, K. & Waldow, T. Expression of the Hippo effectors YAP and TAZ in valvular interstitial cells from porcine aortic valves. Thorac. Cardiovasc. Surg. 62, SC130 (2014).
Katsumi, A., Orr, A. W., Tzima, E. & Schwartz, M. A. Integrins in mechanotransduction. J. Biol. Chem. 279, 12001–12004 (2004).
Trappmann, B. et al. Extracellular-matrix tethering regulates stem-cell fate. Nat. Mater. 11, 642–649 (2012).
Khetan, S. et al. Degradation-mediated cellular traction directs stem cell fate in covalently crosslinked three-dimensional hydrogels. Nat. Mater. 12, 458–465 (2013).
Sacks, M. S. & Yoganathan, A. P. Heart valve function: a biomechanical perspective. Philos. Trans. R. Soc. B Biol. Sci. 362, 1369–1391 (2007).
Sacks, M. S., Schoen, F. J. & Mayer, J. E. Bioengineering challenges for heart valve tissue engineering. Annu. Rev. Biomed. Eng. 11, 289–313 (2009).
Butcher, J. T., Mahler, G. J. & Hockaday, L. A. Aortic valve disease and treatment: the need for naturally engineered solutions. Adv. Drug Deliv. Rev. 63, 242–268 (2011).
Fan, R. & Sacks, M. S. Simulation of planar soft tissues using a structural constitutive model: Finite element implementation and validation. J. Biomech. 47, 2043–2054 (2014).
Yap, C. H., Saikrishnan, N., Tamilselvan, G. & Yoganathan, A. P. Experimental technique of measuring dynamic fluid shear stress on the aortic surface of the aortic valve leaflet. J. Biomech. Eng. 133, 061007 (2011).
Wang, H., Leinwand, L. A. & Anseth, K. S. Roles of transforming growth factor-β1 and OB-cadherin in porcine cardiac valve myofibroblast differentiation. FASEB J. http://dx.doi.org/10.1096/fj.14-254623.
Hutcheson, J. D. et al. Cadherin-11 regulates cell–cell tension necessary for calcific nodule formation by valvular myofibroblasts. Arterioscler. Thromb. Vasc. Biol. 33, 114–120 (2013).
Lee, D. M. et al. Cadherin-11 in synovial lining formation and pathology in arthritis. Science 315, 1006–1010 (2007).
Schneider, D. J. et al. Cadherin-11 contributes to pulmonary fibrosis: potential role in TGF-beta production and epithelial to mesenchymal transition. FASEB J. 26, 503–512 (2012).
Mahler, G. J., Frendl, C. M., Cao, Q. & Butcher, J. T. Effects of shear stress pattern and magnitude on mesenchymal transformation and invasion of aortic valve endothelial cells. Biotechnol. Bioeng. 4, 25291 (2014).
Butcher, J. T. & Nerem, R. M. Valvular endothelial cells regulate the phenotype of interstitial cells in co-culture: effects of steady shear stress. Tissue Eng. 12, 905–915 (2006).
Tseng, H. et al. A three-dimensional co-culture model of the aortic valve using magnetic levitation. Acta Biomater. 10, 173–182 (2014).
Wylie, R. G. et al. Spatially controlled simultaneous patterning of multiple growth factors in three-dimensional hydrogels. Nat. Mater. 10, 799–806 (2011).
DeForest, C. A. & Anseth, K. S. Photoreversible patterning of biomolecules within click-based hydrogels. Angew. Chem. Int. Ed. Engl. 51, 1816–1819 (2012).
Gandavarapu, N. R., Azagarsamy, M. A. & Anseth, K. S. Photo-click living strategy for controlled, reversible exchange of biochemical ligands. Adv. Mater. 26, 2521–2526 (2014).
Kloxin, A. M., Kasko, A. M., Salinas, C. N. & Anseth, K. S. Photodegradable hydrogels for dynamic tuning of physical and chemical properties. Science 324, 59–63 (2009).
Kirschner, C. M., Alge, D. L., Gould, S. T. & Anseth, K. S. Clickable, photodegradable hydrogels to dynamically modulate valvular interstitial cell phenotype. Adv. Healthc. Mater. 3, 649–657 (2014).
Guvendiren, M. & Burdick, J. A. Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics. Nat. Commun. 3, 792 (2012).
Guvendiren, M., Perepelyuk, M., Wells, R. G. & Burdick, J. A. Hydrogels with differential and patterned mechanics to study stiffness-mediated myofibroblastic differentiation of hepatic stellate cells. J. Mech. Behav. Biomed. Mater. 4, 00395–00390 (2013).
We acknowledge K. Barthel, P. Harvey, W. Wan, and K. Mabry (University of Colorado, Boulder, CO, USA) for kindly reading and editing the paper, and W. Wan for assistance in taking images for Figure 3. The authors' research work is supported by NIH research grants R01 GM029090 to L.A.L and the Howard Hughes Medical Institute to K.S.A.
The authors declare no competing financial interests.
About this article
Cite this article
Wang, H., Leinwand, L. & Anseth, K. Cardiac valve cells and their microenvironment—insights from in vitro studies. Nat Rev Cardiol 11, 715–727 (2014). https://doi.org/10.1038/nrcardio.2014.162
Scientific Reports (2020)
Scientific Reports (2020)
Pediatric Cardiology (2020)
The role of fibroblast growth factor 1 and 2 on the pathological behavior of valve interstitial cells in a three-dimensional mechanically-conditioned model
Journal of Biological Engineering (2019)
Journal of Cardiovascular Translational Research (2017)