Novel therapeutic strategies targeting fibroblasts and fibrosis in heart disease

Abstract

Our understanding of the functions of cardiac fibroblasts has moved beyond their roles in heart structure and extracellular matrix generation and now includes their contributions to paracrine, mechanical and electrical signalling during ontogenesis and normal cardiac activity. Fibroblasts also have central roles in pathogenic remodelling during myocardial ischaemia, hypertension and heart failure. As key contributors to scar formation, they are crucial for tissue repair after interventions including surgery and ablation. Novel experimental approaches targeting cardiac fibroblasts are promising potential therapies for heart disease. Indeed, several existing drugs act, at least partially, through effects on cardiac connective tissue. This Review outlines the origins and roles of fibroblasts in cardiac development, homeostasis and disease; illustrates the involvement of fibroblasts in current and emerging clinical interventions; and identifies future targets for research and development.

Figure 1. Key developments and changing focus of cardiac fibroblast research

This timeline shows key articles on cardiac fibroblasts. Early research in this area was predominantly descriptive of histoanatomical structures, then changed to also describing biophysical and biochemical signalling. Since the early 2000s cardiac fibroblast research has also included the roles of fibroblasts in myocyte transdifferentiation as a potential source for regeneration as well as their potential to be utilized to improve scarring. *Embryonic chick heart; ^‡cultured cells from embryonic mouse heart, ^§embryonic rat heart, ^║cultured cells from neonatal rat heart, ^¶cultured cells from embryonic chick heart, ^#adult rat heart, **transgenic rabbit model of hypertrophic cardiomyopathy, ^‡‡humans, ^§§adult rabbit heart, ^║║adult mouse heart. Cx43, connexin 43; EndoMT, endothelial to mesenchymal transition; FGF, fibroblastgrowth factor; MI, myocardial infarction; miRNA, microRNA; RCT, randomized clinical trial; TGFβ, transforming growth factor β. a) Manasek 1969 J Embryol Exp Morphol. 1969,(3):333–48 b) Goshima & Tonomura, Exp Cell Res 1969,56:387–392 c) Markwald et al. Dev Biol. 1975 Jan;42(1): 160–80 d) Rook et al. Pflugers Arch. 1989/414:95–8 e) Potts and Runyan Develop Biol 134, 392, 1989 f) Long et al. Cell Regul 1991,2(12): 1081–95 g) Kohl et al., Exp Physiol 1994,79:943–56 h) Mikawa and Gourdie Develop Biol. 174, 221–232 i) Morabito et al., Develp Biol., 234, 204, 2001 j) Patel et al., Circulation. 2001 Jul 17;104:317–24 k) Assmus et al., Circulation: 2002, 106, 3009–17 l) Perin et al., Circulation: 2003, 107, 2294–302 m) Gaudesius et al. Circ Res 2003, 93:421–8 n) Camelliti et al. Circ Res 2004, 94:828–835 o) Visconti et al., Circ Res 2006, 98:690–6 p) Möllman et al., Cardiovasc Res 2006, 71:661–71 q) Takahashi and Yamanaka, Cell, 126, 2006 663–76 r) Walker et al. J Cardiovasc Electrophysiol. 2007 Aug;18(8):862–8 s) Roell W. et al. Nature 2007, 450, 819–824, t) van Rooij et al., Proc Natl Acad Sci U S A, 2007 105, 13027–32 u) Takeda et al. J Clin Invest, 2009, 120, 254–65 v) Ieda et al, Cell 2010/142: 375–386 w) Moore-Morris et al. J Clin Invest. 2014 Jul;124(7):2921–34

Figure 2. Cardiac fibroblast and myofibroblast origins in health and disease

Cardiac fibroblasts originate from various sources, including the (pro-)epicardium, cardiac endothelium, neural creast and bone marrow. They form amultiplicity of cells, with hitherto ill-defined precursurs (both resident and circulating), subtypes, and relations to pericytes. Fibroblast activation by pathological stimuli, including stretch, hypoxia, and inflammation, lead to phenotype-conversion via proto-myofibrobalsts to myofibroblasts. For detailed explanations, see text.