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Immune cells encounter tissues with vastly different biochemical and physical characteristics. Much of the research emphasis has focused on the role of cytokines and chemokines in regulating immune cell function, but the role of the physical microenvironment has received considerably less attention. The tissue mechanics, or stiffness, of healthy tissues varies dramatically from soft adipose tissue and brain to stiff cartilage and bone. Tissue mechanics also change due to fibrosis and with diseases such as atherosclerosis or cancer. The process by which cells sense and respond to their physical microenvironment is called mechanotransduction. Here we review mechanotransduction in immunologically important diseases and how physical characteristics of tissues regulate immune cell function, with a specific emphasis on mechanoregulation of macrophages and TLR signaling.

YAP/TAZ activity is regulated by a complex network of signals that include the Hippo pathway, cell polarity complexes, and signaling receptors of the RTK, GPCR, and WNT pathways and by a seamlessly expanding number of intracellular cues including energy and mevalonate metabolism. Among these inputs, we here concentrate on mechanical cues embedded in the extracellular matrix (ECM) microenvironment, which are key regulators of YAP/TAZ activity. We review the techniques that have been used to study mechano-regulation of YAP/TAZ, including conceptual and practical considerations on how these experiments should be designed and controlled. Finally, we briefly review the most appropriate techniques to monitor YAP/TAZ activity in these experiments and their significance to study the mechanisms linking YAP/TAZ to mechanical cues.

Migration through constrictions can clearly rupture nuclei and mis-localize nuclear proteins but damage to DNA remains uncertain as does any effect on cell cycle. Here, myosin-II inhibition rescues rupture and partially rescues the DNA damage marker γH2AX, but an apparent delay in cell cycle is unaffected. Co-overexpression of multiple DNA repair factors and antioxidant inhibition of break formation also have partial effects, independent of rupture. Complete rescue of both DNA damage and cell cycle delay by myosin inhibition plus antioxidant reveals a bimodal dependence of cell cycle on DNA damage. Migration through custom-etched pores yields the same bimodal, with ~4-um pores causing intermediate levels of damage and cell cycle delay. Micronuclei (generated in faulty division) of the smallest diameter appear similar to ruptured nuclei, with high DNA damage and entry of chromatin-binding cGAS (cyclic-GMP-AMP-synthase) from cytoplasm but low repair factor levels. Increased genomic variation after constricted migration is quantified in expanding clones and is consistent with (mis)repair of excess DNA damage and subsequent proliferation.

Although it is beyond doubt that mechanical stimulation is crucial to maintain bone mass, its role in preserving bone architecture is much less clear. Commonly, it is assumed that mechanics helps to conserve the trabecular network since an “accidental” thinning of a trabecula due to a resorption event would result in a local increase of load, thereby activating bone deposition there. However, considering that the thin trabecula is part of a network, it is not evident that load concentration happens locally on the weakened trabecula. The aim of this work was to clarify whether mechanical load has a protective role for preserving the trabecular network during remodeling. Trabecular bone is made dynamic by a remodeling algorithm, which results in a thickening/thinning of trabeculae with high/low strain energy density. Our simulations show that larger deviations from a regular cubic lattice result in a greater loss of trabeculae. Around lost trabeculae, the remaining trabeculae are on average thinner. More generally, thin trabeculae are more likely to have thin trabeculae in their neighborhood. The plausible consideration that a thin trabecula concentrates a higher amount of strain energy within itself is therefore only true when considering a single isolated trabecula. Mechano-regulated remodeling within a network-like architecture leads to local concentrations of thin trabeculae., Biomechanics and Modeling in Mechanobiology, 14 (4), ISSN:1617-7959, ISSN:1617-7940

Cardiovascular tissue engineering (CVTE) aims to create living tissues, with the ability to grow and remodel, as replacements for diseased blood vessels and heart valves. Despite promising results, the (long-term) functionality of these engineered tissues still needs improvement to reach broad clinical application. The functionality of native tissues is ensured by their specific mechanical properties directly arising from tissue organization. We therefore hypothesize that establishing a native-like tissue organization is vital to overcome the limitations of current CVTE approaches. To achieve this aim, a better understanding of the growth and remodeling (G&R) mechanisms of cardiovascular tissues is necessary. Cells are the main mediators of tissue G&R, and their behavior is strongly influenced by both mechanical stimuli and cell–cell signaling. An increasing number of signaling pathways has also been identified as mechanosensitive. As such, they may have a key underlying role in regulating the G&R of tissues in response to mechanical stimuli. A more detailed understanding of mechano-regulated cell–cell signaling may thus be crucial to advance CVTE, as it could inspire new methods to control tissue G&R and improve the organization and functionality of engineered tissues, thereby accelerating clinical translation. In this review, we discuss the organization and biomechanics of native cardiovascular tissues; recent CVTE studies emphasizing the obtained engineered tissue organization; and the interplay between mechanical stimuli, cell behavior, and cell–cell signaling. In addition, we review past contributions of computational models in understanding and predicting mechano-regulated tissue G&R and cell–cell signaling to highlight their potential role in future CVTE strategies.