Heterocellular signalling and crosstalk in the heart in ischaemia and heart failure

This editorial is part of the Spotlight Issue on: Heterocellular signalling and crosstalk in the heart in ischaemia and heart failure Although the heart is usually considered to be a homogeneous organ, it is composed of different cell types that closely interact to maintain homoeostasis. Clearly, the largest volume is occupied by cardiomyocytes but, when it comes to numbers, the other cell types take the upper hand. This drives to a delicate and intricate network of interactions that usually support the action of cardiomyocytes and help to maintain organ function. However, who is a friend in healthy conditions, might turn out to be a foe in other situations. In multiple cardiac pathologies, heterotypic intercellular interactions significantly contribute to the evolution of the disease with multiple and often highly sophisticated actions. Knowledge about the details of such dialogue between the contractile machinery and endothelial cells, leucocytes, fibroblasts, adipocytes, or neurons is only now starting to emerge in its full complexity. Given the crucial role of these interactions in the maintenance of tissue integrity and in the response to noxious conditions, this knowledge is of critical translational importance. The large number of the extracellular signals and the intracellular pathways evoked represent potential drug targets. Therefore, the definition of the network of heterotypic cellular interactions in heart diseases is currently an advanced frontier of drug discovery. The current Spotlight issue provides a state-of-the-art description of the cell types involved, the signals produced, and the cellular responses elicited and expands on different concepts, models, and disease conditions, with particular focus on ischaemic heart disease and myocardial infarction, remodelling, and heart failure. The different contributions illustrate the complexity of the system as well as how this intricate network can be tackled. Figure 1 gives an overview of the different cross-talk pathways that are discussed. Heterocellular connections in the heart. Cardiac homoeostasis is supported by an intricate network of interactions between distinct cell types, including not only cardiomyocytes, but also leucocytes, fibroblasts, and endothelial cells. In healthy hearts, cardiomyocyte-endothelial cell communication via oxygen species (ROS) and Neuregulin (Nrg) production is pivotal to angiogenesis, cardiomyocyte survival, and hypertrophy. On the other hand, cytokines mediate the functional crosstalk between fibroblasts and immune cells and ultimately provide feedback control of fibroblast/leucocyte activation. Potential other crosstalk pathways, for example, between cardiomyocytes and fibroblasts or macrophages, exist in a healthy heart but have been omitted for simplicity. For further details, please refer to the specific reviews in this Spotlight issue. In disease conditions, an intense re-organization of these heterocellular connections occurs and initiates a large set of adaptive and maladaptive feedback responses. While Nrg-mediated endothelial cell–cardiomyocyte interaction is protective, injured cardiomyocytes signal to leucocytes, mainly involving M1 macrophages (M1 Mφ), through Damage Associated Molecular Pattern molecules (DAMPs). Similarly, maladaptive are cardiomyocyte-fibroblast connections via RNA molecules (miRNA/lncRNA) and cytokine-based communication between leucocytes and fibroblasts. Furthermore, epicardial adipocytes instruct fibroblasts to transdifferentiate in myofibroblasts and induce fibrosis. On the other hand, M2 macrophages (M2 Mφ) stimulate neovascularization and healing in myocardial infarction. Similarly, mesenchymal stem cells secrete soluble factors suppressing fibroblast/myofibroblast transdifferentiation. Green and red arrows represent adaptive and maladaptive responses, respectively. Although mechanisms for short- and long-distance intercellular interactions have been long studied, the analysis of bidirectional communication between cardiomyocytes and other cell types is a source of continuous discoveries. For example, a previously unsuspected plasticity is emerging in endothelial cells, adipocytes, or macrophages, which sense systemic alterations and bend cardiomyocyte function to their will. In line with this view, the review by Parodi and Kuhn reports on the latest discoveries about the ability of endothelial cells to provide survival and trophic signals to cardiomyocytes via the previously unsuspected production of growth factors of the neuregulin family.1 Along the same line, the review by Hatem and Sanders explains that growth factors such as Activin-A are produced by adipocytes present in the epicardial adipose tissue and are critically involved in the development of cardiac fibrosis.2 Adipose tissue thus plays unforeseen roles, acting not only as a mechanical protection to the heart, but also as a neighbouring endocrine tissue. Thus, in heart failure and its comorbidities, such as diabetes mellitus, adipocytes can drive maladaptive remodelling and significantly contribute to atrial fibrosis and fibrillation. In such pathological conditions, a further balance between adaptive and maladaptive remodelling is provided by the interplay between cardiomyocytes and fibroblasts/myofibroblasts. Fibroblasts represent the most abundant cell type in the heart and their function is often controversial. For example, they help tissue repair after an ischaemic insult but also induce fibrosis, tissue stiffness, and contractile dysfunction. Therefore, understanding their mechanisms of action is of critical importance for future therapeutic strategies. The review by Deb describes that the delicate equilibrium between adaptive and maladaptive functions of fibroblasts might depend on signalling events mediated by Wnt family growth factors and critically evaluates the possibility of Wnt signalling hub modulation for therapy.3 Furthermore, the review by Ramkisoensing et al.4 addresses the critical issue of the crosstalk between resident cardiac cells such as myofibroblasts and mesenchymal stem cells, providing an exhaustive description of the signals that exogenous and endogenous stem cells can exchange with myofibroblasts to fine-tune tissue remodelling and promote post-ischaemic recovery. Nonetheless, a crucial factor in tissue repair is inflammation, causing mobilization of immune cells and their infiltration into the cardiac tissue. Different reviews address the latest discoveries on the relationship between cardiac and immune cells and highlight novel mediators regulating the crosstalk between resident and infiltrating cells. A remarkable example is provided by the versatility of macrophages and their cytokines, equally involved in wound healing, tissue remodelling, and orchestration of the immune response. The review by Fujiu and Nagai5 describes the nature and function of a cardioprotective subset of macrophages resident in the heart, the M2 macrophages. These macrophages show anti-inflammatory activities through inhibition of CD4T cells or secretion of anti-inflammatory cytokines. Nonetheless, the heart also carries M1 macrophages whose nature and role is covered by the review by Frantz and Nahrendorf,6 which illustrates the origin of these cells and the mechanisms they exploit to influence tissue remodelling as well as inflammation resolution. Cardiac fibroblasts and endothelial cells also interact with cardiomyocytes or inflammatory cells and the reviews by Zhang et al.7 and Van Linthout et al.8 address how these interactions influence cardiac physiopathology, through reactive oxygen species and cytokine production, respectively. In these processes, cardiomyocytes are not silent bystanders and their influence over local and remote neighbours appears critical to shape the response to injury or metabolic stress. How cardiomyocytes respond to inflammation is only now starting to emerge and the review by Ghigo et al.9 provides a description of the signal transduction events elicited by cytokines and stress mediators inside cardiomyocytes. Refined studies in genetically modified mouse models indicate that cardiomyocyte-dependent signalling plays a more central role than previously expected in the induction of inflammatory reactions and leucocyte recruitment in the heart. For example, activation inside cardiomyocytes of signal transducers including STAT3 is controlling a large set of adaptive and maladaptive feedback responses and the review by Haghikia et al.10 specifically defines what we know about this critical signal transduction pathway and how this knowledge could be exploited to provide new therapeutic strategies. Besides the use of well characterized cytokines and inflammatory mediators by cardiomyocytes and their neighbours, other means of intercellular communication have attracted increasing attention. Examples are circulating microRNAs (miRNAs) and exosomes, but novel roles for older players are steadily emerging. Viereck et al.11 highlight a series of new secreted factors, ranging from proteins to miRNAs and long non-coding RNAs. They specifically focus on the paracrine cross-talk between cardiomyocytes and cardiac fibroblasts and address how miRNAs might be involved in this interplay. They also summarize novel therapeutic strategies for the treatment of heart failure that target factors mediating pathological communication. Furthermore, Sluijter et al.12 give an elegant overview of the importance of secreted exosomes for cardiovascular biology; for instance, they report how exosomes, secreted from specific stem and progenitor cells, produce beneficial effects in the injured myocardium. These studies may help to develop selected exosome preparations as novel ‘drugs’ treating various forms of ischaemic heart disease. With respect to understanding how to boost intercellular communication to heal the injured heart, Zacchigna and Giacca13 provide a review about both extracellular and intracellular signals that regulate cardiomyocyte proliferation in postnatal life. These cues include selected growth factors but also miRNAs that are able to activate the proliferation machinery of adult non-dividing cardiomyocytes. Such studies may be relevant for the development of novel therapeutic strategies for cardiac regeneration, especially as miRNAs are currently emerging as promising drug targets. Overall, the contributions in this Spotlight issue illustrate how modulation of derailed intercellular communication systems can provide new concepts apt for therapeutic intervention. The importance of these complex ways of interaction to fine-tune heart function in disease is only now starting to emerge and clearly more insights are needed. Despite the recent explosion in knowledge of the non-coding ‘dark’ genome, the possible exploitation of these discoveries for therapeutic strategies and diagnostic/prognostic markers needs much more in depth understanding. For example, a more comprehensive characterization of the secreted miRNome might help to identify the most relevant miRNA. Future applications will likely open the way for both classical medicinal chemistry and less conventional biotechnological approaches. Signalling molecules, such as kinases, transcription factors, and epigenetic regulators, might be modulated by novel small molecules. A more detailed knowledge of the cytokines and growth factors involved in intercellular communication can pave the way for the development of specific injectable antibodies. Although in their infancy, new strategies and technologies coming from an improved knowledge of the network of cellular interactions in the heart are already delineating major breakthroughs and this Spotlight issue is presented to foster future research in the field and progress in clinical application of these concepts. Conflict of interest: E.H. is co-founder of Kither Biotech. E.H. and T.T. received funding from Leducq Foundation.