- Open Access
Cardiac myofibroblasts: cells out of balance. A new thematic series
© Dixon; licensee BioMed Central Ltd. 2012
- Received: 26 July 2012
- Accepted: 30 July 2012
- Published: 3 September 2012
We are pleased to introduce a new thematic series dealing with cardiac fibrosis and its association with cardiovascular diseases. A wide variety of cardiovascular diseases are associated with cardiac fibrosis, which is now widely recognized to be not a secondary, but rather a primary contributor to cardiac dysfunction. The purpose of the current series of papers and reviews is to provide the reader with an up-to-date synopsis of the very latest research results and hypotheses that impact on cardiac fibrosis and disease.
- Cardiac fibrosis
- Cardiac fibroblasts
- Extracellular matrix
Additional file 1: Figure 1 Scratch Assay of Cardiac Myofibroblasts. Time-lapse movie (10 s) of primary rat cardiac myofibroblasts in first passage compressed form 16 hours of incubation in a Zeiss live-cell incubation in a Zeiss live-cel l incubation chamber. Cells are cultured in DMEM/F 12 in the presence of fetal bovine serum. These cells express significant levels of a SMA and ED-A fibronectin proteins that designate them as myofibroblasts. (MP4 6 MB)
What is the difference between healthy cardiac fibroblast function and that of cardiac myofibroblasts? Matrix components of the healthy heart are produced by interstitial cardiac fibroblasts. These cells maintain a relatively slow turnover of fibrillar collagens in normal conditions, but may respond to both mechanical loading and TGF-β1 stimulation[5, 6] by a switch to a myofibroblastic phenotype wherein they express α-smooth muscle actin (αSMA), synonymous with increased contractile force. αSMA expression is increased in myofibroblasts in fibrotic hearts subjected to pressure or volume overload or in the infarct scar of post-MI hearts. Causal factors in this conversion are compressibility of the substrate when ventricular fibroblasts are plated in vitro and overexpression of R-Smads. Enhanced contractility that attends this protein’s expression is believed to be important in allowing these cells to contract while bound to matrix collagens and other proteins, thereby allowing for physical remodeling of the matrix itself. Thus myofibroblasts are the primary mediators of wound healing in the damaged ventricle and we have previously demonstrated that they are the dominant cell type in the infarct scar. Myofibroblasts migrate to the infarct zone, restoring cellularity. Their contraction confers matrix remodeling by imparting tensile force to the matrix, opposes retractile force, promotes scar contraction, activates latent TGF-β1, and reorients collagen fibrils[4, 14–16]. Investigation of these cells in hypertrophied hearts is clinically relevant as they contribute to wound healing, matrix remodeling, and eventual cardiac fibrosis through the elevated production of fibrillar and non-fibrillar collagens[17, 18].
The new thematic series to be published in this journal will touch upon topics not commonly associated with “textbook” knowledge of cardiac fibroblasts. Included in the range of topics in which we will be accepting submissions of novel research papers and review articles are: (1) the role of fibroblast and myofibroblast autophagy in the regulation of cellular function, (2) the relative contribution of migratory stem cells in populating the heart with myofibroblasts vs. endogenous conversion of fibroblasts to myofibroblasts, (3) the roles of pericytes, epithelial-to-mesenchymal transition (EMT), endothelial-to-mesenchymal transition (EndMT), and fibrocytes in influencing cardiac extracellular matrix remodeling in heart disease, (4) microRNA influence on myofibroblast function, (5) novel signaling pathways and mechanotransduction in the regulation of myofibroblast function, (6) exploration of the role of non-collagenous proteins in the cardiac extracellular matrix, (7) developments in MMP and TIMP biology in the heart, (8) valvular interstitial cells and valve disease, and finally, (9) novel aspects of myofibroblast biology. As these areas represent novel concepts in heart disease and cardiac fibrosis and could be described as areas less well-covered in the literature, they are to be our current focus.
Why should clinicians or basic scientists care about these new developments? Part of the answer lies in the novel suggestion that cardiac fibroblasts and myofibroblasts are unique cells, e.g., distinguished by their relative specific phenotype from other fibroblastic cells. While it is well-known that the structural scaffold that exists between myocytes in the heart is composed of extracellular matrix (matrix) and mesenchymal cells and that this matrix provides an exceptionally strong means to tether and coordinate force generated via myocyte contraction, little is known of their regulation. The principal stromal cell type is fibroblasts, but this designation belies their diversity and topographic differentiation from organ to organ including the heart. Thus, the term “fibroblasts” designates a highly heterogeneous group that exhibits distinct differentiated phenotypes in different tissues. The implications of these fundamental differences are unclear. Further, the study of fibroblast and myofibroblast biology in specific organs is an important but relatively understudied area, especially in cardiovascular disease with attendant cardiac fibrosis. Recent novel data indicate that ventricular fibroblast activation and cardiac fibrosis are primary events in ventricular remodeling, rather than a secondary response to cardiomyocyte injury. Thus the traditional role of cardiac fibrosis as a secondary disease modifier has, for the first time, been called into question, and the need to investigate factors that regulate cardiac myofibroblasts in various types of cardiovascular disease is apparent. For these reasons we have sought to publish a series of papers that will highlight the molecular and biochemical properties of these specific cells, and of their functioning in disease. Finally, the field of cardiac fibrosis has experienced a burgeoning level of interest and participation in investigations during the past 5 years, and this series will take advantage of this to showcase the thoughts of what some of the best minds in area are thinking.
This work is supported by a grant-in-aid from the Heart and Stroke Foundation of Manitoba, an operating grant from the Canadian Institutes of Health Research, and the St. Boniface Hospital Research Foundation.
- Liang CC, Park AY, Guan JL: In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc. 2007, 2: 329-333.View ArticlePubMedGoogle Scholar
- Eghbali M, Czaja MJ, Zeydel M, Weiner FR, Zern MA, Seifter S, Blumenfeld OO: Collagen chain mRNAs in isolated heart cells from young and adult rats. J Mol Cell Cardiol. 1988, 20: 267-276. 10.1016/S0022-2828(88)80059-2.View ArticlePubMedGoogle Scholar
- Weber KT: Fibrosis, a common pathway to organ failure: angiotensin II and tissue repair. Semin Nephrol. 1997, 17: 467-491.PubMedGoogle Scholar
- Wang J, Chen H, Seth A, McCulloch CA: Mechanical force regulation of myofibroblast differentiation in cardiac fibroblasts. Am J Physiol Heart Circ Physiol. 2003, 285: H1871-H1881.View ArticlePubMedGoogle Scholar
- Desmouliere A, Geinoz A, Gabbiani F, Gabbiani G: Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol. 1993, 122: 103-111. 10.1083/jcb.122.1.103.View ArticlePubMedGoogle Scholar
- Petrov VV, Fagard RH, Lijnen PJ: Stimulation of collagen production by transforming growth factor-beta1 during differentiation of cardiac fibroblasts to myofibroblasts. Hypertension. 2002, 39: 258-263. 10.1161/hy0202.103268.View ArticlePubMedGoogle Scholar
- Leslie KO, Taatjes DJ, Schwarz J, von Turkovich M, Low RB: Cardiac myofibroblasts express alpha smooth muscle actin during right ventricular pressure overload in the rabbit. Am J Pathol. 1991, 139: 207-216.PubMed CentralPubMedGoogle Scholar
- Hinz B, Celetta G, Tomasek JJ, Gabbiani G, Chaponnier C: Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol Biol Cell. 2001, 12: 2730-2741.PubMed CentralView ArticlePubMedGoogle Scholar
- Masur SK, Dewal HS, Dinh TT, Erenburg I, Petridou S: Myofibroblasts differentiate from fibroblasts when plated at low density. Proc Natl Acad Sci USA. 1996, 93: 4219-4223. 10.1073/pnas.93.9.4219.PubMed CentralView ArticlePubMedGoogle Scholar
- Bujak M, Ren G, Kweon HJ, Dobaczewski M, Reddy A, Taffet G, Wang XF, Frangogiannis NG: Essential Role of Smad3 in Infarct Healing and in the Pathogenesis of Cardiac Remodeling. Circulation. 2007, 116: 2127-2138. 10.1161/CIRCULATIONAHA.107.704197.View ArticlePubMedGoogle Scholar
- Arora PD, McCulloch CA: Dependence of collagen remodelling on alpha-smooth muscle actin expression by fibroblasts. J Cell Physiol. 1994, 159: 161-175. 10.1002/jcp.1041590120.View ArticlePubMedGoogle Scholar
- Peterson DJ, Ju H, Hao J, Panagia M, Chapman DC, Dixon IM: Expression of Gi-2 alpha and Gs alpha in myofibroblasts localized to the infarct scar in heart failure due to myocardial infarction. Cardiovasc Res. 1999, 41: 575-585. 10.1016/S0008-6363(98)00264-8.View ArticlePubMedGoogle Scholar
- Norman D: An exploration of two opposing theories of wound contraction. J Wound Care. 2004, 13: 138-140.View ArticlePubMedGoogle Scholar
- Arany PR, Flanders KC, Kobayashi T, Kuo CK, Stuelten C, Desai KV, Tuan R, Rennard SI, Roberts AB: Smad3 deficiency alters key structural elements of the extracellular matrix and mechanotransduction of wound closure. Proc Natl Acad Sci USA. 2006, 103: 9250-9255. 10.1073/pnas.0602473103.PubMed CentralView ArticlePubMedGoogle Scholar
- Lijnen P, Petrov V, Fagard R: Transforming growth factor-beta 1-mediated collagen gel contraction by cardiac fibroblasts. J Renin Angiotensin Aldosterone Syst. 2003, 4: 113-118. 10.3317/jraas.2003.011.View ArticlePubMedGoogle Scholar
- Wipff PJ, Rifkin DB, Meister JJ, Hinz B: Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J Cell Biol. 2007, 179: 1311-1323. 10.1083/jcb.200704042.PubMed CentralView ArticlePubMedGoogle Scholar
- Cleutjens JP, Verluyten MJ, Smits JF, Daemen MJ: Collagen remodeling after myocardial infarction in the rat heart. Am J Pathol. 1995, 147: 325-338.PubMed CentralPubMedGoogle Scholar
- Shamhart PE, Meszaros JG: Non-fibrillar collagens: Key mediators of post-infarction cardiac remodeling?. J Mol Cell Cardiol. 2009Google Scholar
- Chang HY, Chi JT, Dudoit S, Bondre C, van de RM, Botstein D, Brown PO: Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc Natl Acad Sci USA. 2002, 99: 12877-12882. 10.1073/pnas.162488599.PubMed CentralView ArticlePubMedGoogle Scholar
- Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, Galuppo P, Just S, Rottbauer W, Frantz S, et al: MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature. 2008, 456: 980-984. 10.1038/nature07511.View ArticlePubMedGoogle Scholar
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