This editorial refers to ‘Deletion of delta-like 1 homologue accelerates fibroblast–myofibroblast differentiation and induces myocardial fibrosis’, by P. Rodriguez et al., doi:10.1093/eurheartj/ehy188. Myocardial fibrosis, defined by the diffuse and disproportionate accumulation of collagen type I and III fibres in the interstitium, represents a final common lesion following a variety of myocardial injuries caused by an intrinsic cardiac disease or by systemic factors activated in the context of extracardiac co-morbidities such as arterial hypertension, diabetes mellitus, and chronic kidney disease.1 The accumulation of fibrotic tissue is maladaptive and leads to left ventricular dysfunction, arrhythmia, impaired myocardial oxygen availability, and poor outcomes.1 Although some conventional therapies, such as renin–angiotensin–aldosterone system inhibitors, reduce fibrosis in humans, myocardial fibrosis persists in patients with cardiac diseases, even when they are treated with these agents.1 On the other hand, although a number of emerging therapies targeting myocardial fibrosis are promising in pre-clinical models, many clinical trials of novel antifibrotic drugs have failed due to lack of effectiveness.1 Therefore, novel strategies targeting critical mechanisms of the fibrogenic process are required to treat myocardial fibrosis in an effective manner.1 There are two principal patterns of myocardial fibrosis.2 In reparative or replacement fibrosis, the fibrotic tissue replaces small foci of cardiomyocytes, forming microscars. In reactive fibrosis, accumulation of fibrous tissue occurs within the interstitium and in the perivascular space around intramural coronary arteries, and the perimysium and endomysium around the cardiac muscle bundles and individual cardiomyocytes. Whereas cardiomyocyte death is often the triggering event responsible for the initiation of the fibrotic response in reparative myocardial fibrosis, varied stimuli (e.g., pressure overload, ischaemia, or metabolic injury) may trigger the fibrotic response in the absence of cell death in reactive myocardial fibrosis.3 Although resident fibroblasts, circulating and resident fibroblast progenitor cells including fibrocytes, epicardial epithelial cells undergoing epithelial to mesenchymal transition, and endothelial cells undergoing endothelial to mesenchymal transdifferentiation are all potential sources sources of myofibroblasts, the available evidence supports that myofibroblasts generated from resident fibroblasts undergoing differentiation play an essential role in the fibrotic response to cardiomyocyte death or profibrotic stimuli.4,5 The myofibroblast is a cell which combines ultrastructural and phenotypic characteristics of smooth muscle cells acquired through formation of contractile stress fibres and the expression of alpha smooth muscle actin, with an extensive endoplasmic reticulum, a feature of synthetically active cells.4,5 The myofibroblast’s secretome consists of procollagen types I and III, molecules requisite to regulation of turnover of extracellular fibrillary collagen types I and III, and autocrine and paracrine factors that simulate their metabolic activity, perpetuating fibrogenesis.4,5 Thus the process of cell differentiation leading to the myofibroblast emerges as a key target for antifibrotic strategies. Transforming growth factor-β (TGF-β) has been identified as a primary and potent mediator of myofibroblast generation and fibrosis in the heart.6 During myocardial injury, TGF-β gene expression is up-regulated and the protein is subsequently secreted into the extracellular space by surrounding mesenchymal cells, tissue macrophages and monocytes, and resident fibroblasts. TGF-β binds to its cell surface receptor, a heterodimeric complex consisting of TGF-β receptor type 1 (TGFβ-R1) and 2 (TGFβ-R2). In canonical TGF-β signalling, the transcription factors Smad2/3 become phosphorylated by TGFβ-R1, which permits Smad4 interaction and translocation into the nucleus where they are thought to participate in the transcriptional induction of genes encoding proteins characteristic of both the myofibroblast phenotype and fibrogenesis.7 In this issue of the journal, Rodriguez et al.8 provide evidence supporting a new role for Delta-like homologue 1 (Dlk1) in regulating TGF-β-mediated generation of cardiac myofibroblasts. Dlk1 is a paternally imprinted gene that encodes a transmembrane protein belonging to the epidermal growth factor (EGF)-like family, which includes Notch receptors and their ligands,9 and plays a critical role in controlling cell differentiation processes.10 Using a loss- and gain-of-function approach and different in vitro and in vivo models, Rodriguez et al.8 demonstrate that Dlk1 inhibits cardiac fibroblast to myofibroblast differentiation and fibrosis by interfering with TGF-β/Smad3 signalling in the myocardium. Interestingly, Dlk1 blocks the interaction of TGF-β with TGFβ-R2 via activation of miR-370 mostly in cardiomyocytes and also in fibroblasts. Dlk1 thus emerges as a new target candidate for antifibrotic therapy in cases where aberrant TGF-β signalling leads to myocardial fibrosis (Take home figure). The translational relevance of this possibility is given by the observation from the same authors that the expression of both Dlk1 and miR370 was reduced in ischaemic/fibrotic human hearts and within the scar of infarcted pig myocardium.8 The authors are to be congratulated for identifying a new pathway of differentiation of cardiac fibroblasts into myofibroblasts that can be targetable for an effective reduction of myocardial fibrosis. Take home figure View largeDownload slide Proposed sequence of molecular events triggered by increasing Delta-like homologue 1 (Dlk1) gene in the cardiomyocyte and/or the cardiac fibroblast that would lead to inhibition of the differentiation of the fibroblast into a myofibroblast with the subsequent inhibition of the fibrogenic process and the reduction in myocardial fibrosis. Abbreviations are as given in the text. Take home figure View largeDownload slide Proposed sequence of molecular events triggered by increasing Delta-like homologue 1 (Dlk1) gene in the cardiomyocyte and/or the cardiac fibroblast that would lead to inhibition of the differentiation of the fibroblast into a myofibroblast with the subsequent inhibition of the fibrogenic process and the reduction in myocardial fibrosis. Abbreviations are as given in the text. There are, however, some aspects that deserve to be considered. First, in the injured myocardium, fibroblasts do not simply serve as matrix-producing cells, but may also exert other actions (e.g. stimulate inflammation).11 It thus could be of interest to explore whether Dlk1 targeting influences the cross-talk between fibroblasts and inflammatory and other cardiac cells. Secondly, while much of the fibroblasts/myofibroblast literature focuses on the canonical TGF-β signalling pathway, there is mounting evidence suggesting that non-canonical TGF-β pathway signalling through the TGF-β-activated kinase (TAK1)/TAK1-binding protein/mitogen-activated protein kinase/c-Jun N-terminal kinase/p38 kinase axis may play a more central role in myocardial fibrosis.6 In this regard, it has been reported that the ability of Dlk1 to inhibit the differentiation of mouse embryo fibroblasts into adipocytes is not accompanied by changes in the activity of the downstream enzymes of the axis.12 Whether this is also the case for the ability of Dlk1 to inhibit the differentiation of cardiac fibroblasts into myofibroblasts could be further investigated. Thirdly, it is unclear why Dlk1 is down-regulated in the fibrotic heart,8 as it is how Dlk1 is regulated at the cardiac level, and in different cardiac cells. This is a major pending research issue to consolidate its involvement in myocardial fibrosis. Finally, Dlk1 is alternatively spliced, with transcripts encoding a large, soluble secreted isoform.13 As soluble Dlk1-encoded protein can be measured in human serum,14 it could be worth studying whether the circulating levels of this protein may serve as a biomarker of myocardial Dlk1 in patients with fibrotic cardiac diseases and thus contribute to a more precise phenotyping and personalized antifibrotic therapy of these patients. Conflict of interest: none declared. References 1 González A, Schelbert EB, Díez J, Butler J. Myocardial interstitial fibrosis in heart failure. Biological and translational perspectives. J Am Coll Cardiol 2018; 71: 1696– 1706. Google Scholar CrossRef Search ADS PubMed 2 Weber KT, Pick R, Jalil JE, Janicki JS, Carroll EP. Patterns of myocardial fibrosis. J Mol Cell Cardiol 1989; 21 Suppl 5: 121– 131. Google Scholar CrossRef Search ADS PubMed 3 Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci 2014; 71: 549– 574. Google Scholar CrossRef Search ADS PubMed 4 Shinde AV, Frangogiannis NG. Mechanisms of fibroblast activation in the remodeling myocardium. Curr Pathobiol Rep 2017; 5: 145– 152. Google Scholar CrossRef Search ADS PubMed 5 Weber KT, Sun Y, Bhattacharya SK, Ahokas RA, Gerling IC. Myofibroblast-mediated mechanisms of pathological remodelling of the heart. Nat Rev Cardiol 2013; 10: 15– 26. Google Scholar CrossRef Search ADS PubMed 6 Leask A. TGFbeta, cardiac fibroblasts, and the fibrotic response. Cardiovasc Res 2007; 74: 207– 212. Google Scholar CrossRef Search ADS PubMed 7 Khalil H, Kanisicak O, Prasad V, Correll RN, Fu X, Schips T, Vagnozzi RJ, Liu R, Huynh T, Lee SJ, Karch J, Molkentin JD. Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis. J Clin Invest 2017; 127: 3770– 3783. Google Scholar CrossRef Search ADS PubMed 8 Rodriguez P, Sassi Y, Troncone L, Benard L, Ishikawa K, Gordon RE, Lamas S, Laborda J, Hajjar RJ, Lebeche D. Deletion of delta-like 1 homologue accelerates fibroblast-myofibroblast differentiation and induces myocardial fibrosis. Eur Heart J 2018;doi:10.1093/eurheartj/ehy188. 9 Baladron V, Ruiz-Hidalgo MJ, Nueda ML, Diaz-Guerra MJ, Garcia-Ramirez JJ, Bonvini E, Gubina E, Laborda J. dlk acts as a negative regulator of Notch1 activation through interactions with specific EGF-like repeats. Exp Cell Res 2005; 303: 343– 359. Google Scholar CrossRef Search ADS PubMed 10 Laborda J. The role of the epidermal growth factor-like protein dlk in cell differentiation. Histol Histopathol 2000; 15: 119– 129. Google Scholar PubMed 11 Van Linthout S, Miteva K, Tschöpe C. Crosstalk between fibroblasts and inflammatory cells. Cardiovasc Res 2014; 102: 258– 269. Google Scholar CrossRef Search ADS PubMed 12 Kim KA1, Kim JH, Wang Y, Sul HS. Pref-1 (preadipocyte factor 1) activates the MEK/extracellular signal-regulated kinase pathway to inhibit adipocyte differentiation. Mol Cell Biol 2007; 27: 2294– 2308. Google Scholar CrossRef Search ADS PubMed 13 Smas CM, Green D, Sul HS. Structural characterization and alternate splicing of the gene encoding the preadipocyte EGF-like protein pref-1. Biochemistry 1994; 33: 9257– 9265. Google Scholar CrossRef Search ADS PubMed 14 Chacón MR, Miranda M, Jensen CH, Fernández-Real JM, Vilarrasa N, Gutiérrez C, Näf S, Gomez JM, Vendrell J. Human serum levels of fetal antigen 1 (FA1/Dlk1) increase with obesity, are negatively associated with insulin sensitivity and modulate inflammation in vitro. Int J Obes (Lond) 2008; 32: 1122– 1129. Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: email@example.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
European Heart Journal – Oxford University Press
Published: Jun 2, 2018
It’s your single place to instantly
discover and read the research
that matters to you.
Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.
All for just $49/month
Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly
Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.
Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.
Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.
All the latest content is available, no embargo periods.
“Hi guys, I cannot tell you how much I love this resource. Incredible. I really believe you've hit the nail on the head with this site in regards to solving the research-purchase issue.”Daniel C.
“Whoa! It’s like Spotify but for academic articles.”@Phil_Robichaud
“I must say, @deepdyve is a fabulous solution to the independent researcher's problem of #access to #information.”@deepthiw
“My last article couldn't be possible without the platform @deepdyve that makes journal papers cheaper.”@JoseServera