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
Ngoc Thien Lam1, Ishita Tandon2, Kartik Balachandran2,1
1Cell and Molecular Biology Program, University of Arkansas, Fayetteville, USA
2Department of Biomedical Engineering, University of Arkansas, Fayetteville, USA

Tóm tắt

More than five million Americans suffer from heart valve disease annually, a condition that worsens cardiac function and gradually leads to heart failure if appropriate treatment is not performed on time. Currently no medication can cure heart valve disease, leaving surgical intervention as the only viable option for patients at late stages of cardiac valve disease. Tremendous efforts have been undertaken to elucidate how resident cells in the valves respond to pathological stimulation as well as the underlying mechanisms that regulate these responses, to identify potential therapeutic targets for non-surgical treatment of valvular heart disease. Cardiac valve interstitial cells (VICs) naturally reside in a complex three-dimensional environment under varying hemodynamics, which is difficult to replicate in vitro. As a result, most cell signaling studies in the field have traditionally been conducted on two-dimensional models or in the absence of hemodynamic forces. Previously, we reported the fabrication of a hydrogel scaffold that could be used to culture valve cells under dynamic mechanical stimulation in a valve-mimetic environment. This model, therefore appeared to be suitable for VIC signaling studies as it provided cells a three-dimensional environment with the ability to incorporate mechanical stretching stimulation. Utilizing this model, we investigated the possible role of fibroblast growth factor 1 and 2 (FGF1 and FGF2) via FGFR1 receptor signaling in regulating valve cell activation under physiological (10% stretch) and pathological (20% stretch) mechanical conditions as well as in mediating cell proliferation and metabolism via the Akt/mTOR pathways. We reported that 1) FGF1 and FGF2 treatment was able to maintain the quiescent phenotype of VICs; 2) Cells increased proliferation as determined by optical redox ratios under elevated cyclic stretch via Akt/mTOR pathways; and 3) FGF1 and 2 signaling via the FGFR1 reduced VIC proliferation and activation under elevated cyclic stretch conditions. Overall, these results suggested that targeting FGFR1 receptor signaling may represent a possible therapeutic strategy for preventing heart valve disease progression.

Từ khóa


Tài liệu tham khảo

Wang H, Leinwand LA, Anseth KS. Cardiac valve cells and their microenvironment--insights from in vitro studies. Nat Rev Cardiol. 2014;11(12):715–27.

Marquis-Gravel G, Redfors B, Leon MB, Genereux P. Medical treatment of aortic stenosis. Circulation. 2016;134(22):1766–84.

Clark MA, et al. Clinical and economic outcomes after surgical aortic valve replacement in Medicare patients. Risk Manag Healthc Policy. 2012;5:117–26.

Jian B, et al. Serotonin mechanisms in heart valve disease I: serotonin-induced up-regulation of transforming growth factor-beta1 via G-protein signal transduction in aortic valve interstitial cells. Am J Pathol. 2002;161(6):2111–21.

Xu J, et al. Serotonin mechanisms in heart valve disease II: the 5-HT2 receptor and its signaling pathway in aortic valve interstitial cells. Am J Pathol. 2002;161(6):2209–18.

Balachandran K, et al. Aortic valve cyclic stretch causes increased remodeling activity and enhanced serotonin receptor responsiveness. Ann Thorac Surg. 2011;92(1):147–53.

Liu AC, Gotlieb AI. Transforming growth factor-beta regulates in vitro heart valve repair by activated valve interstitial cells. Am J Pathol. 2008;173(5):1275–85.

Jian B, Narula N, Li QY, Mohler ER 3rd, Levy RJ. Progression of aortic valve stenosis: TGF-beta1 is present in calcified aortic valve cusps and promotes aortic valve interstitial cell calcification via apoptosis. Ann Thorac Surg. 2003;75(2):457–65 discussion 465-456.

Cushing MC, Mariner PD, Liao JT, Sims EA, Anseth KS. Fibroblast growth factor represses Smad-mediated myofibroblast activation in aortic valvular interstitial cells. FASEB J. 2008;22(6):1769–77.

Han L, Gotlieb AI. Fibroblast growth factor-2 promotes in vitro mitral valve interstitial cell repair through transforming growth factor-beta/Smad signaling. Am J Pathol. 2011;178(1):119–27.

Latif N, et al. Modulation of human valve interstitial cell phenotype and function using a fibroblast growth factor 2 formulation. PLoS One. 2015;10(6):e0127844.

Palmen M, et al. Fibroblast growth factor-1 improves cardiac functional recovery and enhances cell survival after ischemia and reperfusion: a fibroblast growth factor receptor, protein kinase C, and tyrosine kinase-dependent mechanism. J Am Coll Cardiol. 2004;44(5):1113–23.

Garbayo E, et al. Catheter-based Intramyocardial injection of FGF1 or NRG1-loaded MPs improves cardiac function in a preclinical model of ischemia-reperfusion. Sci Rep. 2016;6:25932.

Lam NT, Lam H, Sturdivant NM, Balachandran K. Fabrication of a matrigel-collagen semi-interpenetrating scaffold for use in dynamic valve interstitial cell culture. Biomed Mater. 2017;12(4):045013.

Forough R, et al. Role of AKT/PKB signaling in fibroblast growth factor-1 (FGF-1)-induced angiogenesis in the chicken chorioallantoic membrane (CAM). J Cell Biochem. 2005;94(1):109–16.

Priore R, Dailey L, Basilico C. Downregulation of Akt activity contributes to the growth arrest induced by FGF in chondrocytes. J Cell Physiol. 2006;207(3):800–8.

Mavila N, et al. Fibroblast growth factor receptor-mediated activation of AKT-beta-catenin-CBP pathway regulates survival and proliferation of murine hepatoblasts and hepatic tumor initiating stem cells. PLoS One. 2012;7(11):e50401.

Brewer JR, Mazot P, Soriano P. Genetic insights into the mechanisms of Fgf signaling. Genes Dev. 2016;30(7):751–71.

Tandon I, et al. Valve interstitial cell shape modulates cell contractility independent of cell phenotype. J Biomech. 2016;49(14):3289–3297.

Lam NT, Muldoon TJ, Quinn KP, Rajaram N, Balachandran K. Valve interstitial cell contractile strength and metabolic state are dependent on its shape. Integr Biol (Camb). 2016;8(10):1079–89.

Panek RL, et al. In vitro biological characterization and antiangiogenic effects of PD 166866, a selective inhibitor of the FGF-1 receptor tyrosine kinase. J Pharmacol Exp Ther. 1998;286(1):569–77.

Balachandran K, et al. Elevated cyclic stretch and serotonin result in altered aortic valve remodeling via a mechanosensitive 5-HT(2A) receptor-dependent pathway. Cardiovasc Pathol. 2012;21(3):206–13.

Skala M, Ramanujam N. Multiphoton redox ratio imaging for metabolic monitoring in vivo. Methods Mol Biol. 2010;594:155–62.

Horne TE, et al. Dynamic heterogeneity of the heart valve interstitial cell population in mitral valve health and disease. J Cardiovasc Dev Dis. 2015;2(3):214–32.

Yu JS, Cui W. Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development. 2016;143(17):3050–60.

Benton JA, Kern HB, Anseth KS. Substrate properties influence calcification in valvular interstitial cell culture. J Heart Valve Dis. 2008;17(6):689–99.

Wang H, Haeger SM, Kloxin AM, Leinwand LA, Anseth KS. Redirecting valvular myofibroblasts into dormant fibroblasts through light-mediated reduction in substrate modulus. PLoS One. 2012;7(7):e39969.

Wang H, Tibbitt MW, Langer SJ, Leinwand LA, Anseth KS. Hydrogels preserve native phenotypes of valvular fibroblasts through an elasticity-regulated PI3K/AKT pathway. Proc Natl Acad Sci U S A. 2013;110(48):19336–41.

Gotlieb AI, Rosenthal A, Kazemian P. Fibroblast growth factor 2 regulation of mitral valve interstitial cell repair in vitro. J Thorac Cardiovasc Surg. 2002;124(3):591–7.

Porras AM, et al. Robust generation of quiescent porcine valvular interstitial cell cultures. J Am Heart Assoc. 2017;6(3):e005041.

Han L, Gotlieb AI. Fibroblast growth factor-2 promotes in vitro heart valve interstitial cell repair through the Akt1 pathway. Cardiovasc Pathol. 2012;21(5):382–9.

Zhao T, Zhao W, Chen Y, Ahokas RA, Sun Y. Acidic and basic fibroblast growth factors involved in cardiac angiogenesis following infarction. Int J Cardiol. 2011;152(3):307–13.

Liu AC, Joag VR, Gotlieb AI. The emerging role of valve interstitial cell phenotypes in regulating heart valve pathobiology. Am J Pathol. 2007;171(5):1407–18.

Ikeda M, et al. The Akt-mTOR axis is a pivotal regulator of eccentric hypertrophy during volume overload. Sci Rep. 2015;5:15881.

Aoyagi T, Matsui T. Phosphoinositide-3 kinase signaling in cardiac hypertrophy and heart failure. Curr Pharm Des. 2011;17(18):1818–24.

Cheng H, et al. Lysophosphatidylcholine activates the Akt pathway to upregulate extracellular matrix protein production in human aortic valve cells. J Surg Res. 2017;213:243–50.

El Husseini D, et al. P2Y2 receptor represses IL-6 expression by valve interstitial cells through Akt: implication for calcific aortic valve disease. J Mol Cell Cardiol. 2014;72:146–56.

Jones JD, Ramser HE, Woessner AE, Quinn KP. In vivo multiphoton microscopy detects longitudinal metabolic changes associated with delayed skin wound healing. Commun Biol. 2018;1:198.

Quinn KP, et al. Quantitative metabolic imaging using endogenous fluorescence to detect stem cell differentiation. Sci Rep. 2013;3:3432.

Wang HW, Wei YH, Guo HW. Reduced nicotinamide adenine dinucleotide (NADH) fluorescence for the detection of cell death. Anti Cancer Agents Med Chem. 2009;9(9):1012–7.

Dobbin ZC, Landen CN. The importance of the PI3K/AKT/MTOR pathway in the progression of ovarian cancer. Int J Mol Sci. 2013;14(4):8213–27.

Koundouros N, Poulogiannis G. Phosphoinositide 3-kinase/Akt signaling and redox metabolism in Cancer. Front Oncol. 2018;8:160.

Thông tin
Thông tin xuất bản

Journal of Biological Engineering

Thông tin tác giả