Abstract
During embryonic morphogenesis, the heart undergoes a complex series of cellular phenotypic maturations (e.g., transition of myocytes from proliferative to quiescent or maturation of the contractile apparatus), and this involves stiffening of the extracellular matrix (ECM) acting in concert with morphogenetic signals. The maladaptive remodeling of the myocardium, one of the processes involved in determination of heart failure, also involves mechanical cues, with a progressive stiffening of the tissue that produces cellular mechanical damage, inflammation, and ultimately myocardial fibrosis. The assessment of the biomechanical dependence of the molecular machinery (in myocardial and non-myocardial cells) is therefore essential to contextualize the maturation of the cardiac tissue at early stages and understand its pathologic evolution in aging. Because systems to perform multiscale modeling of cellular and tissue mechanics have been developed, it appears particularly novel to design integrated mechano-molecular models of heart development and disease to be tested in ex vivo reconstituted cells/tissue-mimicking conditions. In the present contribution, we will discuss the latest implication of mechanosensing in heart development and pathology, describe the most recent models of cell/tissue mechanics, and delineate novel strategies to target the consequences of heart failure with personalized approaches based on tissue engineering and induced pluripotent stem cell (iPSC) technologies.
Highlights
In recent years, the assessment of biomechanical-dependent molecular machinery has become a new insightful approach to decipher cellular dynamics inside tissues, with implications in morphogenesis, tissue renewal, and pathology progression
Researchers working in the field tried to develop simulation approaches requiring less computational power (Chu and Voth, 2005, 2006, 2007; Marrink et al, 2007; Monticelli et al, 2008; Pfaendtner et al, 2010; Deriu et al, 2012; Bidone et al, 2015). Some of these methods are based on simplified models for describing the protein structure, such as normal mode analysis (NMA) of elastic network models (ENMs) used as a coarse-grained (CG) approach for protein dynamics (Tama et al, 2000; Tama and Sanejouand, 2001; Li and Cui, 2002; Eom et al, 2007; Tatke et al, 2008; Yang and Chng, 2008; Deriu et al, 2010; Cifra et al, 2015)
When human embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC)-CMs were 3D cultured in collagen gels and subjected to static or cyclic mechanical stress; the 3D culture promoted a better differentiation of the seeded progenitors, and mechanical stretch influenced maturation and structure of the differentiated tissue (Ruan et al, 2015)
Summary
The assessment of biomechanical-dependent molecular machinery has become a new insightful approach to decipher cellular dynamics inside tissues, with implications in morphogenesis, tissue renewal, and pathology progression. Confinement of cells into specific geometric patterns resulted in topological chromatin rearrangement due to force-dependent distribution of epigenetically active enzymes [e.g., histone deacetylases (HDACs)], and this may cause permanent opening/compaction of the chromatin in specific gene loci (Jain et al, 2013) This intriguing possibility seems to be linked to the association existing between chromatin and components of the nuclear envelope (e.g., lamins), which, other than a structural function in the nucleus, may have mechanical transduction and topological insulation functions (Stephens et al, 2018). These evidences support an integration of mechanical forces into the wider control mechanism of cell identity and function and establish spatial and mechanical criteria for correct tissue development and homeostasis
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