In cardiac fibrosis, in response to stress or injury, cardiac fibroblasts deposit excessive amounts of collagens which contribute to the development of heart failure. The biochemical stimuli in... Show moreIn cardiac fibrosis, in response to stress or injury, cardiac fibroblasts deposit excessive amounts of collagens which contribute to the development of heart failure. The biochemical stimuli in this process have been extensively studied, but the influence of cyclic deformation on the fibrogenic behavior of cardiac fibroblasts in the ever-beating heart is not fully understood. In fact, most investigated mechanotransduction pathways in cardiac fibroblasts seem to ultimately have profibrotic effects, which leaves an important question in cardiac fibrosis research unanswered: how do cardiac fibroblasts stay quiescent in the ever-beating human heart? In this study, we developed a human cardiac fibrosis-on-a-chip platform and utilized it to investigate if and how cyclic strain affects fibrogenic signaling. The pneumatically actuated platform can expose engineered tissues to controlled strain magnitudes of 0–25% – which covers the entire physiological and pathological strain range in the human heart – and to biochemical stimuli and enables high-throughput screening of multiple samples. Microtissues of human fetal cardiac fibroblasts (hfCF) embedded in gelatin methacryloyl (GelMA) were 3D-cultured on this platform and exposed to strain conditions which mimic the healthy human heart. The results provide evidence of an antifibrotic effect of the applied strain conditions on cardiac fibroblast behavior, emphasizing the influence of biomechanical stimuli on the fibrogenic process and giving a detailed overview of the mechanosensitive pathways and genes involved, which can be used in the development of novel therapies against cardiac fibrosis. Show less
Gartner, T.C.L.B.; Crnko, S.; Leiteris, L.; Adrichem, I. van; Laake, L.W. van; Bouten, C.V.C.; ... ; Hjortnaes, J. 2022
A fundamental process in the development and progression of heart failure is fibrotic remodeling, characterized by excessive deposition of extracellular matrix proteins in response to injury.... Show moreA fundamental process in the development and progression of heart failure is fibrotic remodeling, characterized by excessive deposition of extracellular matrix proteins in response to injury. Currently, therapies that effectively target and reverse cardiac fibrosis are lacking, warranting novel therapeutic strategies and reliable methods to study their effect. Using a gelatin methacryloyl hydrogel, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and human fetal cardiac fibroblasts (hfCF), we developed a multi-cellular mechanically tunable 3D in vitro model of human cardiac fibrosis. This model was used to evaluate the effects of a promising anti-fibrotic drug-pirfenidone-and yields proof-of-concept of the drug testing potential of this platform. Our study demonstrates that pirfenidone has anti-fibrotic effects but does not reverse all TGF-beta 1 induced pro-fibrotic changes, which provides new insights into its mechanism of action. Show less
Meerman, M.; Gartner, T.C.L.B.; Buikema, J.W.; Wu, S.M.; Siddiqi, S.; Bouten, C.V.C.; ... ; Hjortnaes, J. 2021
Radiation-induced cardiovascular disease is a well-known complication of radiation exposure. Over the last few years, planning for deep space missions has increased interest in the effects of space... Show moreRadiation-induced cardiovascular disease is a well-known complication of radiation exposure. Over the last few years, planning for deep space missions has increased interest in the effects of space radiation on the cardiovascular system, as an increasing number of astronauts will be exposed to space radiation for longer periods of time. Research has shown that exposure to different types of particles found in space radiation can lead to the development of diverse cardiovascular disease via fibrotic myocardial remodeling, accelerated atherosclerosis and microvascular damage. Several underlying mechanisms for radiation-induced cardiovascular disease have been identified, but many aspects of the pathophysiology remain unclear. Existing pharmacological compounds have been evaluated to protect the cardiovascular system from space radiation-induced damage, but currently no radioprotective compounds have been approved. This review critically analyzes the effects of space radiation on the cardiovascular system, the underlying mechanisms and potential countermeasures to space radiation-induced cardiovascular disease. Show less
In heart failure, cardiac fibrosis is the result of an adverse remodeling process. Collagen is continuously synthesized in the myocardium in an ongoing attempt of the heart to repair itself. The... Show moreIn heart failure, cardiac fibrosis is the result of an adverse remodeling process. Collagen is continuously synthesized in the myocardium in an ongoing attempt of the heart to repair itself. The resulting collagen depositions act counterproductively, causing diastolic dysfunction and disturbing electrical conduction. Efforts to treat cardiac fibrosis specifically have not been successful and the molecular etiology is only partially understood. The differentiation of quiescent cardiac fibroblasts to extracellular matrix-depositing myofibroblasts is a hallmark of cardiac fibrosis and a key aspect of the adverse remodeling process. This conversion is induced by a complex interplay of biochemical signals and mechanical stimuli. Tissue-engineered 3D models to study cardiac fibroblast behavior in vitro indicate that cyclic strain can activate a myofibroblast phenotype. This raises the question how fibroblast quiescence is maintained in the healthy myocardium, despite continuous stimulation of ultimately profibrotic mechanotransductive pathways. In this review, we will discuss the convergence of biochemical and mechanical differentiation signals of myofibroblasts, and hypothesize how these affect this paradoxical quiescence.Impact statementMechanotransduction pathways of cardiac fibroblasts seem to ultimately be profibrotic in nature, but in healthy human myocardium, cardiac fibroblasts remain quiescent, despite continuous mechanical stimulation. We propose three hypotheses that could explain this paradoxical state of affairs. Furthermore, we provide suggestions for future research, which should lead to a better understanding of fibroblast quiescence and activation, and ultimately to new strategies for the prevention and treatment of cardiac fibrosis and heart failure. Show less
