Antifibrotic therapies to control cardiac fibrosis

Dobaczewski M, de Haan JJ, Frangogiannis NG. The extracellular matrix modulates fibroblast phenotype and function in the infarcted myocardium. J Cardiovasc Transl Res. 2012;5:837–47. Gonzalez A, Ravassa S, Beaumont J, Lopez B, Diez J. New targets to treat the structural remodeling of the myocardium. J Am Coll Cardiol. 2011;58:1833–43. van den Borne SW, Diez J, Blankesteijn WM, Verjans J, Hofstra L, Narula J. Myocardial remodeling after infarction: the role of myofibroblasts. Nat Rev Cardiol. 2010;7:30–7. Yarbrough WM, Mukherjee R, Stroud RE, Rivers WT, Oelsen JM, Dixon JA, et al. Progressive induction of left ventricular pressure overload in a large animal model elicits myocardial remodeling and a unique matrix signature. J Thorac Cardiovasc Surg. 2012;143:215–23. Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci. 2014;71:549–74. Janicki JS, Brower GL, Gardner JD, Chancey AL, Stewart Jr JA. The dynamic interaction between matrix metalloproteinase activity and adverse myocardial remodeling. Heart Fail Rev. 2004;9:33–42. Spinale FG, Janicki JS, Zile MR. Membrane-associated matrix proteolysis and heart failure. Circ Res. 2013;112:195–208. Tsuruda T, Costello-Boerrigter LC, Burnett Jr JC. Matrix metalloproteinases: pathways of induction by bioactive molecules. Heart Fail Rev. 2004;9:53–61. Creemers EE, Pinto YM. Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart. Cardiovasc Res. 2011;89:265–72. Leask A. Getting to the heart of the matter: new insights into cardiac fibrosis. Circ Res. 2015;116:1269–76. Nag AC. Study of non-muscle cells of the adult mammalian heart: a fine structural analysis and distribution. Cytobios. 1980;28:41–61. Shinde AV, Frangogiannis NG. Fibroblasts in myocardial infarction: a role in inflammation and repair. J Mol Cell Cardiol. 2014;70:74–82. Willems IE, Havenith MG, De Mey JG, Daemen MJ. The alpha-smooth muscle actin-positive cells in healing human myocardial scars. Am J Pathol. 1994;145:868–75. Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med. 1994;1:71–81. Chesney J, Bucala R. Peripheral blood fibrocytes: novel fibroblast-like cells that present antigen and mediate tissue repair. Biochem Soc Trans. 1997;25:520–4. Mori L, Bellini A, Stacey MA, Schmidt M, Mattoli S. Fibrocytes contribute to the myofibroblast population in wounded skin and originate from the bone marrow. Exp Cell Res. 2005;304:81–90. Aiba S, Tagami H. Inverse correlation between CD34 expression and proline-4-hydroxylase immunoreactivity on spindle cells noted in hypertrophic scars and keloids. J Cutan Pathol. 1997;24:65–9. Jain R, Shaul PW, Borok Z, Willis BC. Endothelin-1 induces alveolar epithelial-mesenchymal transition through endothelin type A receptor-mediated production of TGF-beta1. Am J Respir Cell Mol Biol. 2007;37:38–47. Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest. 2003;112:1776–84. Doerner AM, Zuraw BL. TGF-beta1 induced epithelial to mesenchymal transition (EMT) in human bronchial epithelial cells is enhanced by IL-1beta but not abrogated by corticosteroids. Respir Res. 2009;10:1465–9921. Yamauchi Y, Kohyama T, Takizawa H, Kamitani S, Desaki M, Takami K, et al. Tumor necrosis factor-alpha enhances both epithelial-mesenchymal transition and cell contraction induced in A549 human alveolar epithelial cells by transforming growth factor-beta1. Exp Lung Res. 2010;36:12–24. Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med. 2007;13:952–61. Maleszewska M, Moonen JR, Huijkman N, van de Sluis B, Krenning G, Harmsen MC. IL-1beta and TGFbeta2 synergistically induce endothelial to mesenchymal transition in an NFkappaB-dependent manner. Immunobiology. 2013;218:443–54. Dai H, Huang H, Wang SL, Xu X, Jian Y, Cui WH, et al. Role of tumor necrosis factor alpha in endothelial-mesenchymal transition in vitro. Zhonghua Shao Shang Za Zhi. 2012;28:19–24. Tan SM, Zhang Y, Connelly KA, Gilbert RE, Kelly DJ. Targeted inhibition of activin receptor-like kinase 5 signaling attenuates cardiac dysfunction following myocardial infarction. Am J Physiol Heart Circ Physiol. 2010;298:H1415–25. Sun Y, Zhang JQ, Zhang J, Ramires FJ. Angiotensin II, transforming growth factor-beta1 and repair in the infarcted heart. J Mol Cell Cardiol. 1998;30:1559–69. Yu CM, Tipoe GL, Wing-Hon Lai K, Lau CP. Effects of combination of angiotensin-converting enzyme inhibitor and angiotensin receptor antagonist on inflammatory cellular infiltration and myocardial interstitial fibrosis after acute myocardial infarction. J Am Coll Cardiol. 2001;38:1207–15. Campbell SE, Katwa LC. Angiotensin II stimulated expression of transforming growth factor-beta1 in cardiac fibroblasts and myofibroblasts. J Mol Cell Cardiol. 1997;29:1947–58. Gao X, He X, Luo B, Peng L, Lin J, Zuo Z. Angiotensin II increases collagen I expression via transforming growth factor-beta1 and extracellular signal-regulated kinase in cardiac fibroblasts. Eur J Pharmacol. 2009;606:115–20. Ma F, Li Y, Jia L, Han Y, Cheng J, Li H, et al. Macrophage-stimulated cardiac fibroblast production of IL-6 is essential for TGF beta/Smad activation and cardiac fibrosis induced by angiotensin II. PLoS One. 2012;7:e35144. De Mello WC, Specht P. Chronic blockade of angiotensin II AT1-receptors increased cell-to-cell communication, reduced fibrosis and improved impulse propagation in the failing heart. J Renin Angiotensin Aldosterone Syst. 2006;7:201–5. Shibasaki Y, Nishiue T, Masaki H, Tamura K, Matsumoto N, Mori Y, et al. Impact of the angiotensin II receptor antagonist, losartan, on myocardial fibrosis in patients with end-stage renal disease: assessment by ultrasonic integrated backscatter and biochemical markers. Hypertens Res. 2005;28:787–95. Ortiz LA, Lasky J, Gozal E, Ruiz V, Lungarella G, Cavarra E, et al. Tumor necrosis factor receptor deficiency alters matrix metalloproteinase 13/tissue inhibitor of metalloproteinase 1 expression in murine silicosis. Am J Respir Crit Care Med. 2001;163:244–52. Westermann D, Rutschow S, Van Linthout S, Linderer A, Bucker-Gartner C, Sobirey M, et al. Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus. Diabetologia. 2006;49:2507–13. Wilson SS, Ayaz SI, Levy PD. Relaxin: a novel agent for the treatment of acute heart failure. Pharmacotherapy. 2015;35:315–27. Turner NA, Porter KE, Smith WH, White HL, Ball SG, Balmforth AJ. Chronic beta2-adrenergic receptor stimulation increases proliferation of human cardiac fibroblasts via an autocrine mechanism. Cardiovasc Res. 2003;57:784–92. Porter KE, Turner NA, O’Regan DJ, Balmforth AJ, Ball SG. Simvastatin reduces human atrial myofibroblast proliferation independently of cholesterol lowering via inhibition of RhoA. Cardiovasc Res. 2004;61:745–55. Blackburn NJ, Sofrenovic T, Kuraitis D, Ahmadi A, McNeill B, Deng C, et al. Timing underpins the benefits associated with injectable collagen biomaterial therapy for the treatment of myocardial infarction. Biomaterials. 2015;39:182–92. Deng B, Shen L, Wu Y, Shen Y, Ding X, Lu S, et al. Delivery of alginate-chitosan hydrogel promotes endogenous repair and preserves cardiac function in rats with myocardial infarction. J Biomed Mater Res A. 2015;103:907–18. Bridges AW, García AJ. Anti-inflammatory polymeric coatings for implantable biomaterials and devices. J Diabetes Sci Technol. 2008;2:984–94. Wang F, Guan J. Cellular cardiomyoplasty and cardiac tissue engineering for myocardial therapy. Adv Drug Deliv Rev. 2010;62:784–97. Wang RM, Christman KL. Decellularized myocardial matrix hydrogels: In basic research and preclinical studies. Adv Drug Deliv Rev. 2016;96:77–82. Turner NA. Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs). J Mol Cell Cardiol. 2015;94:189. Nakamura T, Matsumoto K, Mizuno S, Sawa Y, Matsuda H, Nakamura T. Hepatocyte growth factor prevents tissue fibrosis, remodeling, and dysfunction in cardiomyopathic hamster hearts. Am J Physiol Heart Circ Physiol. 2005;288:H2131–9. McDade JK, Brennan-Pierce EP, Ariganello MB, Labow RS, Michael LJ. Interactions of U937 macrophage-like cells with decellularized pericardial matrix materials: influence of crosslinking treatment. Acta Biomater. 2013;9:7191–9. Sonnenberg SB, Rane AA, Liu CJ, Rao N, Agmon G, Suarez S, et al. Delivery of an engineered HGF fragment in an extracellular matrix-derived hydrogel prevents negative LV remodeling post-myocardial infarction. Biomaterials. 2015;45:56–63. Yoshizumi T, Zhu Y, Jiang H, D’Amore A, Sakaguchi H, Tchao J, et al. Timing effect of intramyocardial hydrogel injection for positively impacting left ventricular remodeling after myocardial infarction. Biomaterials. 2016;83:182–93. Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation. 2000;101:2981–8. Lahera V, Cachofeiro V, de Las Heras N. Interplay of hypertension, inflammation, and angiotensin II. Am J Hypertens. 2011;24:1059. Haudek SB, Cheng J, Du J, Wang Y, Hermosillo-Rodriguez J, Trial J, et al. Monocytic fibroblast precursors mediate fibrosis in angiotensin-II-induced cardiac hypertrophy. J Mol Cell Cardiol. 2010;49:499–507. Bodiga S, Zhong JC, Wang W, Basu R, Lo J, Liu GC, et al. Enhanced susceptibility to biomechanical stress in ACE2 null mice is prevented by loss of the p47(phox) NADPH oxidase subunit. Cardiovasc Res. 2011;91:151–61. Holmes JW, Borg TK, Covell JW. Structure and mechanics of healing myocardial infarcts. Annu Rev Biomed Eng. 2005;7:223–53. Vu TD, Pal SN, Ti LK, Martinez EC, Rufaihah AJ, Ling LH, et al. An autologous platelet-rich plasma hydrogel compound restores left ventricular structure, function and ameliorates adverse remodeling in a minimally invasive large animal myocardial restoration model: a translational approach: Vu and Pal “Myocardial Repair: PRP, Hydrogel and Supplements”. Biomaterials. 2015;45:27–35. Kobayashi H, Minatoguchi S, Yasuda S, Bao N, Kawamura I, Iwasa M, et al. Post-infarct treatment with an erythropoietin-gelatin hydrogel drug delivery system for cardiac repair. Cardiovasc Res. 2008;79:611–20. Taniyama Y, Morishita R, Aoki M, Hiraoka K, Yamasaki K, Hashiya N, et al. Angiogenesis and antifibrotic action by hepatocyte growth factor in cardiomyopathy. Hypertension. 2002;40:47–53. Futamatsu H, Suzuki J, Mizuno S, Koga N, Adachi S, Kosuge H, et al. Hepatocyte growth factor ameliorates the progression of experimental autoimmune myocarditis: a potential role for induction of T helper 2 cytokines. Circ Res. 2005;96:823–30. Nakamura T, Sakai K, Nakamura T, Matsumoto K. Hepatocyte growth factor twenty years on: Much more than a growth factor. J Gastroenterol Hepatol. 2011;26 Suppl 1:188–202. Ueda H, Nakamura T, Matsumoto K, Sawa Y, Matsuda H, Nakamura T. A potential cardioprotective role of hepatocyte growth factor in myocardial infarction in rats. Cardiovasc Res. 2001;51:41–50. Nakamura T, Mizuno S, Matsumoto K, Sawa Y, Matsuda H, Nakamura T. Myocardial protection from ischemia/reperfusion injury by endogenous and exogenous HGF. J Clin Invest. 2000;106:1511–9. Li Y, Takemura G, Kosai K, Yuge K, Nagano S, Esaki M, et al. Postinfarction treatment with an adenoviral vector expressing hepatocyte growth factor relieves chronic left ventricular remodeling and dysfunction in mice. Circulation. 2003;107:2499–506. Nakano J, Marui A, Muranaka H, Masumoto H, Noma H, Tabata Y, et al. Effects of hepatocyte growth factor in myocarditis rats induced by immunization with porcine cardiac myosin. Interact Cardiovasc Thorac Surg. 2014;18:300–7. Ross J, Gherardi E, Mallorqui-Fernandez N, Bocci M, Sobkowicz A, Rees M, et al. Protein engineered variants of hepatocyte growth factor/scatter factor promote proliferation of primary human hepatocytes and in rodent liver. Gastroenterology. 2012;142:897–906. Jones 2nd DS, Tsai PC, Cochran JR. Engineering hepatocyte growth factor fragments with high stability and activity as Met receptor agonists and antagonists. Proc Natl Acad Sci U S A. 2011;108:13035–40. Liu CJ, Jones 2nd DS, Tsai PC, Venkataramana A, Cochran JR. An engineered dimeric fragment of hepatocyte growth factor is a potent c-MET agonist. FEBS Lett. 2014;588:4831–7. Ruvinov E, Harel-Adar T, Cohen S. Bioengineering the infarcted heart by applying bio-inspired materials. J Cardiovasc Transl Res. 2011;4:559–74. Ruvinov E, Leor J, Cohen S. The promotion of myocardial repair by the sequential delivery of IGF-1 and HGF from an injectable alginate biomaterial in a model of acute myocardial infarction. Biomaterials. 2011;32:565–78. Salimath AS, Phelps EA, Boopathy AV, Che PL, Brown M, Garcia AJ, et al. Dual delivery of hepatocyte and vascular endothelial growth factors via a protease-degradable hydrogel improves cardiac function in rats. PLoS One. 2012;7:e50980. Samuel SM, Akita Y, Paul D, Thirunavukkarasu M, Zhan L, Sudhakaran PR, et al. Coadministration of adenoviral vascular endothelial growth factor and angiopoietin-1 enhances vascularization and reduces ventricular remodeling in the infarcted myocardium of type 1 diabetic rats. Diabetes. 2010;59:51–60. Zentilin L, Puligadda U, Lionetti V, Zacchigna S, Collesi C, Pattarini L, et al. Cardiomyocyte VEGFR-1 activation by VEGF-B induces compensatory hypertrophy and preserves cardiac function after myocardial infarction. FASEB J. 2010;24:1467–78. Ishiguro S, Akasaka Y, Kiguchi H, Suzuki T, Imaizumi R, Ishikawa Y, et al. Basic fibroblast growth factor induces down-regulation of alpha-smooth muscle actin and reduction of myofibroblast areas in open skin wounds. Wound Repair Regen. 2009;17:617–25. Shirakihara T, Horiguchi K, Miyazawa K, Ehata S, Shibata T, Morita I, et al. TGF-beta regulates isoform switching of FGF receptors and epithelial-mesenchymal transition. EMBO J. 2011;30:783–95. 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;22:1769–77. Svystonyuk DA, Ngu JM, Mewhort HE, Lipon BD, Teng G, Guzzardi DG, et al. Fibroblast growth factor-2 regulates human cardiac myofibroblast-mediated extracellular matrix remodeling. J Transl Med. 2015;13:147. Santiago JJ, McNaughton LJ, Koleini N, Ma X, Bestvater B, Nickel BE, et al. High molecular weight fibroblast growth factor-2 in the human heart is a potential target for prevention of cardiac remodeling. PLoS One. 2014;9:e97281. Souders CA, Bowers SL, Baudino TA. Cardiac fibroblast: the renaissance cell. Circ Res. 2009;105:1164–76. Banquet S, Gomez E, Nicol L, Edwards-Levy F, Henry JP, Cao R, et al. Arteriogenic therapy by intramyocardial sustained delivery of a novel growth factor combination prevents chronic heart failure. Circulation. 2011;124:1059–69. Fan YH, Dong H, Pan Q, Cao YJ, Li H, Wang HC. Notch signaling may negatively regulate neonatal rat cardiac fibroblast-myofibroblast transformation. Physiol Res. 2011;60:739–48. Boopathy AV, Martinez MD, Smith AW, Brown ME, Garcia AJ, Davis ME. Intramyocardial delivery of Notch ligand-containing hydrogels improves cardiac function and angiogenesis following infarction. Tissue Eng Part A. 2015;21:2315–22. Forrester JS, Makkar RR, Marban E. Long-term outcome of stem cell therapy for acute myocardial infarction: right results, wrong reasons. J Am Coll Cardiol. 2009;53:2270–2. Don CW, Murry CE. Improving survival and efficacy of pluripotent stem cell-derived cardiac grafts. J Cell Mol Med. 2013;17:1355–62. Tang YL, Wang YJ, Chen LJ, Pan YH, Zhang L, Weintraub NL. Cardiac-derived stem cell-based therapy for heart failure: progress and clinical applications. Exp Biol Med (Maywood). 2013;238:294–300. Garbern JC, Lee RT. Cardiac stem cell therapy and the promise of heart regeneration. Cell Stem Cell. 2013;12:689–98. Rosen MR, Myerburg RJ, Francis DP, Cole GD, Marban E. Translating stem cell research to cardiac disease therapies: pitfalls and prospects for improvement. J Am Coll Cardiol. 2014;64:922–37. van Berlo JH, Molkentin JD. An emerging consensus on cardiac regeneration. Nat Med. 2014;20:1386–93. Nagaya N, Kangawa K, Itoh T, Iwase T, Murakami S, Miyahara Y, et al. Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy. Circulation. 2005;112:1128–35. Gnecchi M, He H, Noiseux N, Liang OD, Zhang L, Morello F, et al. Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J. 2006;20:661–9. Ripa RS, Haack-Sorensen M, Wang Y, Jorgensen E, Mortensen S, Bindslev L, et al. Bone marrow derived mesenchymal cell mobilization by granulocyte-colony stimulating factor after acute myocardial infarction: results from the Stem Cells in Myocardial Infarction (STEMMI) trial. Circulation. 2007;116:I24–30. Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP, et al. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol. 2009;54:2277–86. Traverse JH, McKenna DH, Harvey K, Jorgenso BC, Olson RE, Bostrom N, et al. Results of a phase 1, randomized, double-blind, placebo-controlled trial of bone marrow mononuclear stem cell administration in patients following ST-elevation myocardial infarction. Am Heart J. 2010;160:428–34. Duran JM, Makarewich CA, Sharp TE, Starosta T, Zhu F, Hoffman NE, et al. Bone-derived stem cells repair the heart after myocardial infarction through transdifferentiation and paracrine signaling mechanisms. Circ Res. 2013;113:539–52. Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation. 2002;105:93–8. Balana B, Nicoletti C, Zahanich I, Graf EM, Christ T, Boxberger S, et al. 5-Azacytidine induces changes in electrophysiological properties of human mesenchymal stem cells. Cell Res. 2006;16:949–60. Qian Q, Qian H, Zhang X, Zhu W, Yan YM, Ye SQ, et al. 5-azacytidine induces cardiac differentiation of human umbilical cord-derived mesenchymal stem cells by activating extracellular regulated kinase. Stem Cells Dev. 2012;21:67–75. Wang CC, Chen CH, Lin WW, Hwang SM, Hsieh PCH, Lai PH, et al. Direct intramyocardial injection of mesenchymal stem cell sheet fragments improves cardiac functions after infarction. Cardiovasc Res. 2008;77:515–24. Martinez EC, Kofidis T. Adult stem cells for cardiac tissue engineering. J Mol Cell Cardiol. 2011;50:312–9. Perin EC, Tian M, Marini FC, Silva GV, Zheng Y, Baimbridge F, et al. Imaging long-term fate of intramyocardially implanted mesenchymal stem cells in a porcine myocardial infarction model. Plos One. 2011;6:e22949. Pittenger MF, Martin BJ. Mesenchymal stem cells and their potential as cardiac therapeutics. Circ Res. 2004;95:9–20. Mias C, Lairez O, Trouche E, Roncalli J, Calise D, Seguelas MH, et al. Mesenchymal stem cells promote matrix metalloproteinase secretion by cardiac fibroblasts and reduce cardiac ventricular fibrosis after myocardial infarction. Stem Cells. 2009;27:2734–43. Zuo S, Jones WK, Li HX, He ZS, Pasha ZS, Yang YT, et al. Paracrine effect of Wnt11-overexpressing mesenchymal stem cells on ischemic injury. Stem Cells Dev. 2012;21:598–608. Mazo M, Planat-Benard V, Abizanda G, Pelacho B, Leobon B, Gavira JJ, et al. Transplantation of adipose derived stromal cells is associated with functional improvement in a rat model of chronic myocardial infarction. Eur J Heart Fail. 2008;10:454–62. Mazo M, Hernandez S, Gavira JJ, Abizanda G, Arana M, Lopez-Martinez T, et al. Treatment of reperfused ischemia with adipose-derived stem cells in a preclinical Swine model of myocardial infarction. Cell Transplant. 2012;21:2723–33. Shevchenko EK, Makarevich PI, Tsokolaeva ZI, Boldyreva MA, Sysoeva VY, Tkachuk VA, et al. Transplantation of modified human adipose derived stromal cells expressing VEGF165 results in more efficient angiogenic response in ischemic skeletal muscle. J Transl Med. 2013;11:138. Rigol M, Solanes N, Roura S, Roque M, Novensa L, Dantas AP, et al. Allogeneic adipose stem cell therapy in acute myocardial infarction. Eur J Clin Invest. 2014;44:83–92. Hosoda T, Zheng H, Cabral-da-Silva M, Sanada F, Ide-Iwata N, Ogorek B, et al. Human cardiac stem cell differentiation is regulated by a mircrine mechanism. Circulation. 2011;123:1287–96. Chugh AR, Beache GM, Loughran JH, Mewton N, Elmore JB, Kajstura J, et al. Administration of cardiac stem cells in patients with ischemic cardiomyopathy: the SCIPIO trial: surgical aspects and interim analysis of myocardial function and viability by magnetic resonance. Circulation. 2012;126:S54–64. Bolli R, Tang XL, Sanganalmath SK, Rimoldi O, Mosna F, Abdel-Latif A, et al. Intracoronary delivery of autologous cardiac stem cells improves cardiac function in a porcine model of chronic ischemic cardiomyopathy. Circulation. 2013;128:122–31. Latham N, Ye B, Jackson R, Lam BK, Kuraitis D, Ruel M, et al. Human blood and cardiac stem cells synergize to enhance cardiac repair when cotransplanted into ischemic myocardium. Circulation. 2013;128:S105–12. Williams AR, Hatzistergos KE, Addicott B, McCall F, Carvalho D, Suncion V, et al. Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction. Circulation. 2013;127:213–23. Spater D, Abramczuk MK, Buac K, Zangi L, Stachel MW, Clarke J, et al. A HCN4+ cardiomyogenic progenitor derived from the first heart field and human pluripotent stem cells. Nat Cell Biol. 2013;15:1098–106. Nsair A, Schenke-Layland K, Van Handel B, Evseenko D, Kahn M, Zhao P, et al. Characterization and therapeutic potential of induced pluripotent stem cell-derived cardiovascular progenitor cells. PLoS One. 2012;7:e45603. Hudson J, Titmarsh D, Hidalgo A, Wolvetang E, Cooper-White J. Primitive cardiac cells from human embryonic stem cells. Stem Cells Dev. 2012;21:1513–23. Smith RR, Barile L, Cho HC, Leppo MK, Hare JM, Messina E, et al. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation. 2007;115:896–908. Davis DR, Zhang Y, Smith RR, Cheng K, Terrovitis J, Malliaras K, et al. Validation of the cardiosphere method to culture cardiac progenitor cells from myocardial tissue. PLoS One. 2009;4:e7195. Johnston PV, Sasano T, Mills K, Evers R, Lee ST, Smith RR, et al. Engraftment, differentiation, and functional benefits of autologous cardiosphere-derived cells in porcine ischemic cardiomyopathy. Circulation. 2009;120:1075–83. Chimenti I, Smith RR, Li TS, Gerstenblith G, Messina E, Giacomello A, et al. Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice. Circ Res. 2010;106:971–80. Mishra R, Vijayan K, Colletti EJ, Harrington DA, Matthiesen TS, Simpson D, et al. Characterization and functionality of cardiac progenitor cells in congenital heart patients. Circulation. 2011;123:364–73. Li TS, Cheng K, Malliaras K, Smith RR, Zhang Y, Sun B, et al. Direct comparison of different stem cell types and subpopulations reveals superior paracrine potency and myocardial repair efficacy with cardiosphere-derived cells. J Am Coll Cardiol. 2012;59:942–53. Maxeiner H, Mufti S, Krehbiehl N, Dulfer F, Helmig S, Schneider J, et al. Interleukin-6 contributes to the paracrine effects of cardiospheres cultured from human, murine and rat hearts. J Cell Physiol. 2014;229:1681–9. Xie Y, Ibrahim A, Cheng K, Wu Z, Liang W, Malliaras K, et al. Importance of cell-cell contact in the therapeutic benefits of cardiosphere-derived cells. Stem Cells. 2014;32:2397–406. Davis DR, Kizana E, Terrovitis J, Barth AS, Zhang YQ, Smith RR, et al. Isolation and expansion of functionally-competent cardiac progenitor cells directly from heart biopsies. J Mol Cell Cardiol. 2010;49:312–21. Davis DR, Zhang YQ, Smith RR, Cheng K, Terrovitis J, Malliaras K, et al. Validation of the cardiosphere method to culture cardiac progenitor cells from myocardial tissue. Plos One. 2009;4. Lee ST, White AJ, Matsushita S, Malliaras K, Steenbergen C, Zhang Y, et al. Intramyocardial injection of autologous cardiospheres or cardiosphere-derived cells preserves function and minimizes adverse ventricular remodeling in pigs with heart failure post-myocardial infarction. J Am Coll Cardiol. 2011;57:455–65. Sun CK, Zhen YY, Leu S, Tsai TH, Chang LT, Sheu JJ, et al. Direct implantation versus platelet-rich fibrin-embedded adipose-derived mesenchymal stem cells in treating rat acute myocardial infarction. Int J Cardiol. 2014;14:00440–9. Arana M, Gavira JJ, Pena E, Gonzalez A, Abizanda G, Cilla M, et al. Epicardial delivery of collagen patches with adipose-derived stem cells in rat and minipig models of chronic myocardial infarction. Biomaterials. 2014;35:143–51. Ohnishi S, Sumiyoshi H, Kitamura S, Nagaya N. Mesenchymal stem cells attenuate cardiac fibroblast proliferation and collagen synthesis through paracrine actions. FEBS Lett. 2007;581:3961–6. Xia Y, Zhu K, Lai H, Lang M, Xiao Y, Lian S, et al. Enhanced infarct myocardium repair mediated by thermosensitive copolymer hydrogel-based stem cell transplantation. Exp Biol Med (Maywood). 2015;240:593–600. Ceccaldi C, Bushkalova R, Alfarano C, Lairez O, Calise D, Bourin P, et al. Evaluation of polyelectrolyte complex-based scaffolds for mesenchymal stem cell therapy in cardiac ischemia treatment. Acta Biomater. 2014;10:901–11. Fiumana E, Pasquinelli G, Foroni L, Carboni M, Bonafe F, Orrico C, et al. Localization of mesenchymal stem cells grafted with a hyaluronan-based scaffold in the infarcted heart. J Surg Res. 2013;179:e21–9. Engler AJ, Carag-Krieger C, Johnson CP, Raab M, Tang HY, Speicher DW, et al. Embryonic cardiomyocytes beat best on a matrix with heart-like elasticity: scar-like rigidity inhibits beating. J Cell Sci. 2008;121:3794–802. Nelson DM, Baraniak PR, Ma Z, Guan J, Mason NS, Wagner WR. Controlled release of IGF-1 and HGF from a biodegradable polyurethane scaffold. Pharm Res. 2011;28:1282–93. Tamama K, Kawasaki H, Kerpedjieva SS, Guan J, Ganju RK, Sen CK. Differential roles of hypoxia inducible factor subunits in multipotential stromal cells under hypoxic condition. J Cell Biochem. 2011;112:804–17. Guo X, Elliott CG, Li Z, Xu Y, Hamilton DW, Guan J. Creating 3D angiogenic growth factor gradients in fibrous constructs to guide fast angiogenesis. Biomacromolecules. 2012;13:3262–71. Li Z, Guo X, Guan J. A thermosensitive hydrogel capable of releasing bFGF for enhanced differentiation of mesenchymal stem cell into cardiomyocyte-like cells under ischemic conditions. Biomacromolecules. 2012;13:1956–64. Wang F, Li Z, Khan M, Tamama K, Kuppusamy P, Wagner WR, et al. Injectable, rapid gelling and highly flexible hydrogel composites as growth factor and cell carriers. Acta Biomater. 2010;6:1978–91. Wang F, Li Z, Tamama K, Sen CK, Guan J. Fabrication and characterization of prosurvival growth factor releasing, anisotropic scaffolds for enhanced mesenchymal stem cell survival/growth and orientation. Biomacromolecules. 2009;10:2609–18. Li Z, Guo X, Guan J. An oxygen release system to augment cardiac progenitor cell survival and differentiation under hypoxic condition. Biomaterials. 2012;33:5914–23.