Abstract
Purpose of Review
Activated fibroblasts are critically implicated in repair and remodeling of the injured heart. This manuscript discusses recent progress in the cell biology of fibroblasts in the infarcted and remodeling myocardium, highlighting advances in understanding the origin, function, and mechanisms of activation of these cells.
Recent Findings
Following myocardial injury, fibroblasts undergo activation and myofibroblast transdifferentiation. Recently published studies have suggested that most activated myofibroblasts in the infarcted and pressure-overloaded hearts are derived from resident fibroblast populations. In the healing infarct, fibroblasts undergo dynamic phenotypic alterations in response to changes in the cytokine milieu and in the composition of the extracellular matrix. Fibroblasts do not simply serve as matrix-producing cells, but may also regulate inflammation, modulate cardiomyocyte survival and function, mediate angiogenesis, and contribute to phagocytosis of dead cells.
Summary
In the injured myocardium, fibroblasts are derived predominantly from resident populations and serve a wide range of functions.
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References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Christiansen MN, Kober L, Weeke P, Vasan RS, Jeppesen JL, Smith JG et al (2017) Age-specific trends in incidence, mortality and comorbidities of heart failure in Denmark 1995-2012. Circulation. doi:10.1161/CIRCULATIONAHA.116.025941
Chen J, Hsieh AF, Dharmarajan K, Masoudi FA, Krumholz HM (2013) National trends in heart failure hospitalization after acute myocardial infarction for Medicare beneficiaries: 1998-2010. Circulation 128(24):2577–2584. doi:10.1161/CIRCULATIONAHA.113.003668
Kong P, Christia P, Frangogiannis NG (2014) The pathogenesis of cardiac fibrosis. Cell Mol Life Sci 71(4):549–574
Berk BC, Fujiwara K, Lehoux S (2007) ECM remodeling in hypertensive heart disease. J Clin Invest 117(3):568–575
Shinde AV, Frangogiannis NG (2014) Fibroblasts in myocardial infarction: a role in inflammation and repair. J Mol Cell Cardiol 70C:74–82
Souders CA, Bowers SL, Baudino TA (2009) Cardiac fibroblast: the renaissance cell. Circ Res 105(12):1164–1176
Turner NA, Porter KE (2013) Function and fate of myofibroblasts after myocardial infarction. Fibrogenesis Tissue Repair 6(1):5. doi:10.1186/1755-1536-6-5
Dobaczewski M, de Haan JJ, Frangogiannis NG (2012) The extracellular matrix modulates fibroblast phenotype and function in the infarcted myocardium. J Cardiovasc Transl Res 5(6):837–847
Cleutjens JP, Verluyten MJ, Smiths JF, Daemen MJ (1995) Collagen remodeling after myocardial infarction in the rat heart. Am J Pathol 147(2):325–338
•• Kanisicak O, Khalil H, Ivey MJ, Karch J, Maliken BD, Correll RN et al (2016) Genetic lineage tracing defines myofibroblast origin and function in the injured heart. Nat Commun 7:12260. doi:10.1038/ncomms12260 This study used a wide range of lineage tracing experiments to investigate the cellular origin of activated myofibroblasts in healing myocardial infarction.
Frangogiannis NG (2016) The functional pluralism of fibroblasts in the infarcted myocardium. Circ Res 119(10):1049–1051. doi:10.1161/CIRCRESAHA.116.309926
Woodall MC, Woodall BP, Gao E, Yuan A, Koch WJ (2016) Cardiac fibroblast GRK2 deletion enhances contractility and remodeling following ischemia/reperfusion injury. Circ Res 119(10):1116–1127. doi:10.1161/CIRCRESAHA.116.309538
Saxena A, Chen W, Su Y, Rai V, Uche OU, Li N et al (2013) IL-1 induces Proinflammatory leukocyte infiltration and regulates fibroblast phenotype in the infarcted myocardium. J Immunol 191(9):4838–4848
Nag AC (1980) Study of non-muscle cells of the adult mammalian heart: a fine structural analysis and distribution. Cytobios 28(109):41–61
• Pinto AR, Ilinykh A, Ivey MJ, Kuwabara JT, D’Antoni ML, Debuque R et al (2016) Revisiting cardiac cellular composition. Circ Res 118(3):400–409. doi:10.1161/CIRCRESAHA.115.307778 A robust and systematic characterization of the cellular composition of the adult mouse heart.
Ieda M, Tsuchihashi T, Ivey KN, Ross RS, Hong TT, Shaw RM et al (2009) Cardiac fibroblasts regulate myocardial proliferation through beta1 integrin signaling. Dev Cell 16(2):233–244
Frangogiannis NG (2015) Pathophysiology of myocardial infarction. Compr Physiol 5(4):1841–1875. doi:10.1002/cphy.c150006
Frangogiannis NG (2012) Regulation of the inflammatory response in cardiac repair. Circ Res 110(1):159–173
Chen W, Frangogiannis NG (2013) Fibroblasts in post-infarction inflammation and cardiac repair. Biochim Biophys Acta 1833(4):945–953
Frangogiannis NG (2016) Fibroblast-extracellular matrix interactions in tissue fibrosis. Curr Pathobiol Rep 4(1):11–18. doi:10.1007/s40139-016-0099-1
Prabhu SD, Frangogiannis NG (2016) The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis. Circ Res 119(1):91–112. doi:10.1161/CIRCRESAHA.116.303577
Epelman S, Liu PP, Mann DL (2015) Role of innate and adaptive immune mechanisms in cardiac injury and repair. Nat Rev Immunol 15(2):117–129. doi:10.1038/nri3800
Dewald O, Zymek P, Winkelmann K, Koerting A, Ren G, Abou-Khamis T et al (2005) CCL2/monocyte chemoattractant protein-1 regulates inflammatory responses critical to healing myocardial infarcts. Circ Res 96(8):881–889
van Nieuwenhoven FA, Hemmings KE, Porter KE, Turner NA (2013) Combined effects of interleukin-1alpha and transforming growth factor-beta1 on modulation of human cardiac fibroblast function. Matrix Biol 32(7–8):399–406. doi:10.1016/j.matbio.2013.03.008
Zymek P, Nah DY, Bujak M, Ren G, Koerting A, Leucker T et al (2007) Interleukin-10 is not a critical regulator of infarct healing and left ventricular remodeling. Cardiovasc Res 74(2):313–322
Chen W, Saxena A, Li N, Sun J, Gupta A, Lee DW et al (2012) Endogenous IRAK-M attenuates postinfarction remodeling through effects on macrophages and fibroblasts. Arterioscler Thromb Vasc Biol 32(11):2598–2608
Shinde AV, Humeres C, Frangogiannis NG (2017) The role of alpha-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling. Biochim Biophys Acta 1863(1):298–309. doi:10.1016/j.bbadis.2016.11.006
Frangogiannis NG, Michael LH, Entman ML (2000) Myofibroblasts in reperfused myocardial infarcts express the embryonic form of smooth muscle myosin heavy chain (SMemb). Cardiovasc Res 48(1):89–100
Kaur H, Takefuji M, Ngai CY, Carvalho J, Bayer J, Wietelmann A et al (2016) Targeted ablation of Periostin-expressing activated fibroblasts prevents adverse cardiac remodeling in mice. Circ Res 118(12):1906–1917. doi:10.1161/CIRCRESAHA.116.308643
Nakaya M, Watari K, Tajima M, Nakaya T, Matsuda S, Ohara H et al (2017) Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction. J Clin Invest 127(1):383–401. doi:10.1172/JCI83822
•• Bang C, Batkai S, Dangwal S, Gupta SK, Foinquinos A, Holzmann A et al (2014) Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J Clin Invest 124(5):2136–2146. doi:10.1172/JCI70577 The study documents effects of fibroblasts in regulation of cardiomyocyte hypertrophy, mediated through secretion of miRNA-rich exosomes.
• Ubil E, Duan J, Pillai IC, Rosa-Garrido M, Wu Y, Bargiacchi F et al (2014) Mesenchymal-endothelial transition contributes to cardiac neovascularization. Nature 514(7524):585–590. doi:10.1038/nature13839 This study suggests that fibroblasts exhibit remarkable plasticity and may generate endothelial cells contributing to neovessel formation.
Krenning G, Zeisberg EM, Kalluri R (2010) The origin of fibroblasts and mechanism of cardiac fibrosis. J Cell Physiol 225(3):631–637. doi:10.1002/jcp.22322
Aisagbonhi O, Rai M, Ryzhov S, Atria N, Feoktistov I, Hatzopoulos AK (2011) Experimental myocardial infarction triggers canonical Wnt signaling and endothelial-to-mesenchymal transition. Dis Model Mech 4(4):469–483. doi:10.1242/dmm.006510
Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E et al (2007) Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 13(8):952–961
Mollmann H, Nef HM, Kostin S, von Kalle C, Pilz I, Weber M et al (2006) Bone marrow-derived cells contribute to infarct remodelling. Cardiovasc Res 71(4):661–671
•• Ali SR, Ranjbarvaziri S, Talkhabi M, Zhao P, Subat A, Hojjat A et al (2014) Developmental heterogeneity of cardiac fibroblasts does not predict pathological proliferation and activation. Circ Res 115(7):625–635. doi:10.1161/CIRCRESAHA.115.303794 A systematic and well-documented investigation on the cellular origins of activated fibroblasts in remodeling pressure-overloaded hearts.
•• Moore-Morris T, Guimaraes-Camboa N, Banerjee I, Zambon AC, Kisseleva T, Velayoudon A et al (2014) Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis. J Clin Invest 124(7):2921–2934. doi:10.1172/JCI74783 This study identified resident fibroblast populations as the main cellular source of activated fibroblasts in the remodeling pressure-overloaded myocardium.
Kong P, Christia P, Saxena A, Su Y, Frangogiannis NG (2013) Lack of specificity of fibroblast-specific protein 1 in cardiac remodeling and fibrosis. Am J Physiol Heart Circ Physiol 305(9):H1363–H1372
Ruiz-Villalba A, Simon AM, Pogontke C, Castillo MI, Abizanda G, Pelacho B et al (2015) Interacting resident epicardium-derived fibroblasts and recruited bone marrow cells form myocardial infarction scar. J Am Coll Cardiol 65(19):2057–2066. doi:10.1016/j.jacc.2015.03.520
Zhou B, Honor LB, He H, Ma Q, Oh JH, Butterfield C et al (2011) Adult mouse epicardium modulates myocardial injury by secreting paracrine factors. J Clin Invest 121(5):1894–1904. doi:10.1172/JCI45529
van Amerongen MJ, Bou-Gharios G, Popa E, van Ark J, Petersen AH, van Dam GM et al (2008) Bone marrow-derived myofibroblasts contribute functionally to scar formation after myocardial infarction. J Pathol 214(3):377–386
Fujita J, Mori M, Kawada H, Ieda Y, Tsuma M, Matsuzaki Y et al (2007) Administration of granulocyte colony-stimulating factor after myocardial infarction enhances the recruitment of hematopoietic stem cell-derived myofibroblasts and contributes to cardiac repair. Stem Cells 25(11):2750–2759. doi:10.1634/stemcells.2007-0275
Yano T, Miura T, Ikeda Y, Matsuda E, Saito K, Miki T et al (2005) Intracardiac fibroblasts, but not bone marrow derived cells, are the origin of myofibroblasts in myocardial infarct repair. Cardiovasc Pathol 14(5):241–246
• Kramann R, Schneider RK, DiRocco DP, Machado F, Fleig S, Bondzie PA et al (2015) Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis. Cell Stem Cell 16(1):51–66. doi:10.1016/j.stem.2014.11.004 This study documents the contribution of Gli1+ pericytes as a source of activated myofibroblasts in the injured myocardium and in other fibrotic tissues.
Carlson S, Helterline D, Asbe L, Dupras S, Minami E, Farris S et al (2016) Cardiac macrophages adopt profibrotic/M2 phenotype in infarcted hearts: role of urokinase plasminogen activator. J Mol Cell Cardiol. doi:10.1016/j.yjmcc.2016.05.016
Nevers T, Salvador AM, Grodecki-Pena A, Knapp A, Velazquez F, Aronovitz M et al (2015) Left ventricular T-cell recruitment contributes to the pathogenesis of heart failure. Circ Heart Fail 8(4):776–787. doi:10.1161/CIRCHEARTFAILURE.115.002225
Saxena A, Dobaczewski M, Rai V, Haque Z, Chen W, Li N et al (2014) Regulatory T cells are recruited in the infarcted mouse myocardium and may modulate fibroblast phenotype and function. Am J Physiol Heart Circ Physiol 307(8):H1233–H1242. doi:10.1152/ajpheart.00328.2014
Shiraishi M, Shintani Y, Shintani Y, Ishida H, Saba R, Yamaguchi A et al (2016) Alternatively activated macrophages determine repair of the infarcted adult murine heart. J Clin Invest 126(6):2151–2166. doi:10.1172/JCI85782
Frangogiannis NG (2012) Matricellular proteins in cardiac adaptation and disease. Physiol Rev 92(2):635–688
Sassi Y, Ahles A, Truong DJ, Baqi Y, Lee SY, Husse B et al (2014) Cardiac myocyte-secreted cAMP exerts paracrine action via adenosine receptor activation. J Clin Invest 124(12):5385–5397. doi:10.1172/JCI74349
Ju H, Zhao S, Jassal DS, Dixon IM (1997) Effect of AT1 receptor blockade on cardiac collagen remodeling after myocardial infarction. Cardiovasc Res 35(2):223–232
van den Borne SW, Isobe S, Zandbergen HR, Li P, Petrov A, Wong ND et al (2009) Molecular imaging for efficacy of pharmacologic intervention in myocardial remodeling. JACC Cardiovasc Imaging 2(2):187–198. doi:10.1016/j.jcmg.2008.11.011
Hayashi M, Tsutamoto T, Wada A, Tsutsui T, Ishii C, Ohno K et al (2003) Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents post-infarct left ventricular remodeling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterior acute myocardial infarction. Circulation 107(20):2559–2565
Ciulla MM, Paliotti R, Esposito A, Diez J, Lopez B, Dahlof B et al (2004) Different effects of antihypertensive therapies based on losartan or atenolol on ultrasound and biochemical markers of myocardial fibrosis: results of a randomized trial. Circulation 110(5):552–557. doi:10.1161/01.CIR.0000137118.47943.5C
Dobaczewski M, Chen W, Frangogiannis NG (2011) Transforming growth factor (TGF)-beta signaling in cardiac remodeling. J Mol Cell Cardiol 51(4):600–606
Dewald O, Ren G, Duerr GD, Zoerlein M, Klemm C, Gersch C et al (2004) Of mice and dogs: species-specific differences in the inflammatory response following myocardial infarction. Am J Pathol 164(2):665–677
Xia Y, Dobaczewski M, Gonzalez-Quesada C, Chen W, Biernacka A, Li N et al (2011) Endogenous thrombospondin 1 protects the pressure-overloaded myocardium by modulating fibroblast phenotype and matrix metabolism. Hypertension 58(5):902–911
Frangogiannis NG, Ren G, Dewald O, Zymek P, Haudek S, Koerting A et al (2005) The critical role of endogenous thrombospondin (TSP)-1 in preventing expansion of healing myocardial infarcts. Circulation 111(22):2935–2942
Bujak M, Ren G, Kweon HJ, Dobaczewski M, Reddy A, Taffet G et al (2007) Essential role of Smad3 in infarct healing and in the pathogenesis of cardiac remodeling. Circulation 116:2127–2138
Dobaczewski M, Bujak M, Li N, Gonzalez-Quesada C, Mendoza LH, Wang XF et al (2010) Smad3 signaling critically regulates fibroblast phenotype and function in healing myocardial infarction. Circ Res 107(3):418–428
Koitabashi N, Danner T, Zaiman AL, Pinto YM, Rowell J, Mankowski J et al (2011) Pivotal role of cardiomyocyte TGF-beta signaling in the murine pathological response to sustained pressure overload. J Clin Invest 121(6):2301–2312
Nishida M, Onohara N, Sato Y, Suda R, Ogushi M, Tanabe S et al (2007) Galpha12/13-mediated up-regulation of TRPC6 negatively regulates endothelin-1-induced cardiac myofibroblast formation and collagen synthesis through nuclear factor of activated T cells activation. J Biol Chem 282(32):23117–23128. doi:10.1074/jbc.M611780200
•• Davis J, Burr AR, Davis GF, Birnbaumer L, Molkentin JD (2012) A TRPC6-dependent pathway for myofibroblast transdifferentiation and wound healing in vivo. Dev Cell 23(4):705–715 This study provides the first in vivo demonstration of an important role for TRPC6 in myofibroblast activation in healing wounds.
Du J, Xie J, Zhang Z, Tsujikawa H, Fusco D, Silverman D et al (2010) TRPM7-mediated Ca2+ signals confer fibrogenesis in human atrial fibrillation. Circ Res 106(5):992–1003. doi:10.1161/CIRCRESAHA.109.206771
Adapala RK, Thoppil RJ, Luther DJ, Paruchuri S, Meszaros JG, Chilian WM et al (2013) TRPV4 channels mediate cardiac fibroblast differentiation by integrating mechanical and soluble signals. J Mol Cell Cardiol 54:45–52. doi:10.1016/j.yjmcc.2012.10.016
Saxena A, Bujak M, Frunza O, Dobaczewski M, Gonzalez-Quesada C, Lu B et al (2014) CXCR3-independent actions of the CXC chemokine CXCL10 in the infarcted myocardium and in isolated cardiac fibroblasts are mediated through proteoglycans. Cardiovasc Res 103(2):217–227. doi:10.1093/cvr/cvu138
Bujak M, Dobaczewski M, Gonzalez-Quesada C, Xia Y, Leucker T, Zymek P et al (2009) Induction of the CXC chemokine interferon-gamma-inducible protein 10 regulates the reparative response following myocardial infarction. Circ Res 105(10):973–983
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Arti Shinde and Nikolaos Frangogiannis declare that they have no conflicts of interest.
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This article does not contain any studies with human or animal subjects performed by any of the authors.
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Supported by grants from the National Institutes of Health (R01 HL76246 and R01 HL85440 to N.G.F.), the Department of Defense (PR151134 and PR151029 to N.G.F.) and a post-doctoral award by the American Heart Association Founders’ affiliate (to A.V.S.).
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This article is part of the Topical Collection on Activated Myofibroblasts and Fibrosis in Various Organs
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Shinde, A.V., Frangogiannis, N.G. Mechanisms of Fibroblast Activation in the Remodeling Myocardium. Curr Pathobiol Rep 5, 145–152 (2017). https://doi.org/10.1007/s40139-017-0132-z
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DOI: https://doi.org/10.1007/s40139-017-0132-z