Macrophage immune cells exist on a plastic spectrum of phenotypes governed by their physical and biochemical environment. Controlling macrophage function to facilitate immunological regeneration or fighting pathology has emerged as a therapeutic possibility. The rate-limiting step in translating macrophage immunomodulation therapies has been the absence of fundamental knowledge of how physics and biochemistry in the macrophage microenvironment converge to inform phenotype. In this review we explore recent trends in bioengineered model systems that integrate physical and biochemical variables applied to macrophage mechanosensing and plasticity. We focus on how tuning of mechanical forces and biomaterial composition orchestrate macrophage function in physiological and pathological contexts. Ultimately, a broader understanding of stimuli-responsiveness in macrophages leads to informed design for future modulatory therapies.

Stretch-shortening cycles (SSCs) involve muscle lengthening (eccentric contractions) instantly followed by shortening (concentric contractions). This combination enhances force, work, and power output compared to pure shortening (SHO), which is known as SSC-effect. Recent evidence indicates both cross-bridge-based (XB) and non-cross-bridge-based (non-XB, e.g., titin) structures contribute to this effect. This study analyzed force re-development following SSCs and SHO to gain further insight into the roles of XB and non-XB structures regarding the SSC-effect. Experiments were conducted on rat soleus muscle fibres (n=16) with different SSC velocities (30%, 60%, 85% of maximum shortening velocity) and constant stretch-shortening magnitudes (18% of optimum length). The XB inhibitor blebbistatin was used to distinguish between XB and non-XB contributions to force generation. Results showed SSCs led to significantly greater (1.02±.15 vs. 0.68±.09 [ΔF/Δt]; t(62)=8.61, p<.001, d=2.79) and faster (75 ms vs. 205 [ms]; t(62) = -6.37, p<.001, d=-1.48) force re-development compared to SHO in the control treatment. In the blebbistatin treatment, SSCs still resulted in greater (.11±.03 vs. .06±.01 [ΔF/Δt]; t(62) = 8.00, p<.001, d=2.24) and faster (3010±1631 vs. 7916±3230 [ms]; t(62) = -8.00, p<.001, d=-1.92) force re-development compared to SHO. These findings deepen our understanding of the SSC-effect, underscoring the involvement of non-XB structures like titin in modulating force production. This modulation likely involves complex mechanosensory coupling from stretch to signal transmission during muscle contraction.

Mechanosensing, or how cells sense and respond to the physical environment, is crucial for many aspects of biological function, ranging from cell movement during development to cancer metastasis, the immune response and gene expression driving cell fate determination. Relevant physical stimuli include the stiffness of the extracellular matrix, contractile forces, shear flows in blood vessels, complex topography of the cellular microenvironment and membrane protein mobility. Although mechanosensing has been more widely studied in non-immune cells, it has become increasingly clear that physical cues profoundly affect the signaling function of cells of the immune system. In this Review, we summarize recent studies on mechanical regulation of immune cells, specifically lymphocytes, and explore how the force-generating cytoskeletal machinery might mediate mechanosensing. We discuss general principles governing mechanical regulation of lymphocyte function, spanning from the molecular scale of receptor activation to cellular responses to mechanical stimuli.

Filopodia, widely distributed on cell surfaces, are distinguished by their dynamic extensions, playing pivotal roles in a myriad of biological processes. Their functions span from mechanosensing and guidance to cell-cell communication during cellular organization in the early embryo. Filopodia have significant roles in pathogenic processes, such as cancer invasion and viral dissemination. Molecular mapping of the filopodome has revealed generic components essential for filopodia functions. In parallel, recent insights into biophysical mechanisms governing filopodia dynamics have provided the foundation for broader investigations of filopodia\'s biological functions. We highlight recent discoveries of engagement of filopodia in various stages of development and pathogenesis and present an overview of intricate molecular and physical features of these cellular structures across a spectrum of cellular activities.

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It is remarkable how teeth maintain their healthy condition under exceptionally high levels of mechanical loading. This suggests the presence of inherent mechanical adaptation mechanisms within their structure to counter constant stress. Dentin, situated between enamel and pulp, plays a crucial role in mechanically supporting tooth function. Its intermediate stiffness and viscoelastic properties, attributed to its mineralized, nanofibrous extracellular matrix, provide flexibility, strength, and rigidity, enabling it to withstand mechanical loading without fracturing. Moreover, dentin\'s unique architectural features, such as odontoblast processes within dentinal tubules and spatial compartmentalization between odontoblasts in dentin and sensory neurons in pulp, contribute to a distinctive sensory perception of external stimuli while acting as a defensive barrier for the dentin-pulp complex. Since dentin\'s architecture governs its functions in nociception and repair in response to mechanical stimuli, understanding dentin mechanobiology is crucial for developing treatments for pain management in dentin-associated diseases and dentin-pulp regeneration. This review discusses how dentin\'s physical features regulate mechano-sensing, focusing on mechano-sensitive ion channels. Additionally, we explore advanced in vitro platforms that mimic dentin\'s physical features, providing deeper insights into fundamental mechanobiological phenomena and laying the groundwork for effective mechano-therapeutic strategies for dentinal diseases.

Hair, or hair-like fibrillar structures, are ubiquitous in biology, from fur on the bodies of mammals, over trichomes of plants, to the mastigonemes on the flagella of single-celled organisms. While these long and slender protuberances are passive, they are multifunctional and help to mediate interactions with the environment. They provide thermal insulation, sensory information, reversible adhesion, and surface modulation (e.g., superhydrophobicity). This review will present various functions that biological hairs have been discovered to carry out, with the hairs spanning across six orders of magnitude in size, from the millimeter-thick fur of mammals down to the nanometer-thick fibrillar ultrastructures on bateriophages. The hairs are categorized according to their functions, including protection (e.g., thermal regulation and defense), locomotion, feeding, and sensing. By understanding the versatile functions of biological hairs, bio-inspired solutions may be developed across length scales.

OBJECTIVE: Diabetes and hypertension are important risk factors for vascular disease, including atherosclerosis. A driving factor in this process is lipid accumulation in smooth muscle cells of the vascular wall. The glucose- and mechano-sensitive transcriptional coactivator, myocardin-related transcription factor A (MRTF-A/MKL1) can promote lipid accumulation in cultured human smooth muscle cells and contribute to the formation of smooth muscle-derived foam cells. The purpose of this study was to determine if intact human blood vessels ex vivo can be used to evaluate lipid accumulation in the vascular wall, and if this process is dependent on MRTF and/or galectin-3/LGALS3. Galectin-3 is an early marker of smooth muscle transdifferentiation and a potential mediator for foam cell formation and atherosclerosis.
RESULTS: Human mammary arteries and saphenous veins were exposed to altered cholesterol and glucose levels in an organ culture model. Accumulation of lipids, quantified by Oil Red O, was increased by cholesterol loading and elevated glucose concentrations. Pharmacological inhibition of MRTF with CCG-203971 decreased lipid accumulation, whereas adenoviral-mediated overexpression of MRTF-A had the opposite effect. Cholesterol-induced expression of galectin-3 was decreased after inhibition of MRTF. Importantly, pharmacological inhibition of galectin-3 with GB1107 reduced lipid accumulation in the vascular wall after cholesterol loading.
CONCLUSIONS: Ex vivo organ culture of human arteries and veins can be used to evaluate lipid accumulation in the intact vascular wall, as well as adenoviral transduction and pharmacological inhibition. Although MRTF and galectin-3 may have beneficial, anti-inflammatory effects under certain circumstances, our results, which demonstrate a significant decrease in lipid accumulation, support further evaluation of MRTF- and galectin-3-inhibitors for therapeutic intervention against atherosclerotic vascular disease.

As the cytoskeleton sustains cell and tissue forces, it incurs physical damage that must be repaired to maintain mechanical homeostasis. The LIM-domain protein zyxin detects force-induced ruptures in actin-myosin stress fibers, coordinating downstream repair factors to restore stress fiber integrity through unclear mechanisms. Here, we reconstitute stress fiber repair with purified proteins, uncovering detailed links between zyxin\'s force-regulated binding interactions and cytoskeletal dynamics. In addition to binding individual tensed actin filaments (F-actin), zyxin\'s LIM domains form force-dependent assemblies that bridge broken filament fragments. Zyxin assemblies engage repair factors through multi-valent interactions, coordinating nucleation of new F-actin by VASP and its crosslinking into aligned bundles by ɑ-actinin. Through these combined activities, stress fiber repair initiates within the cores of micron-scale damage sites in cells, explaining how these F-actin depleted regions are rapidly restored. Thus, zyxin\'s force-dependent organization of actin repair machinery inherently operates at the network scale to maintain cytoskeletal integrity.

The fibrous extracellular matrix (ECM) is vital for tissue regeneration and impacts implanted device treatments. Previous research on fibrous biomaterials shows varying cellular reactions to surface orientation, often due to unclear interactions between surface topography and substrate elasticity. Our study addresses this gap by achieving the rapid creation of hydrogels with diverse fibrous topographies and varying substrate moduli through a surface printing strategy. Cells exhibit heightened traction force on nanopatterned soft hydrogels, particularly with randomly distributed patterns compared with regular soft hydrogels. Meanwhile, on stiff hydrogels featuring an aligned topography, optimal cellular mechanosensing is observed compared to random topography. Mechanistic investigations highlight that cellular force-sensing and adhesion are influenced by the interplay of pattern deformability and focal adhesion orientation, subsequently mediating stem cell differentiation. Our findings highlight the importance of combining substrate modulus and topography to guide cellular behavior in designing advanced tissue engineering biomaterials.