Podosomes are specialized, highly dynamic adhesion structures protruding from the membrane of animal cells. Their complex ultrastructure enables interactions with the microenvironment and extracellular matrix and the sensory and mechano-effector functions. Although historically attributed to monocytes, macrophages, and dendric cells, podosomes also occur in osteoclasts, endothelial cells, muscle, neural, cancer, and other cell types. This review describes podosome structure and podosomes' role in mechanotransduction and beyond.
Wound healing is a complex biological process that restores the integrity and strength of the skin. Keratinocytes and fibroblasts play pivotal roles in tissue repair through their interactions and signaling pathways. Keratinocytes proliferate to re-epithelialize the wound, while fibroblasts contribute to the formation of new extracellular matrix. Although cell proliferation is essential for wound healing, excessive proliferation can lead to scar formation. Therefore, strategies that balance proliferation and migration, along with proper mechanotransduction, are crucial for efficient wound repair. Sheep and camel milk contain numerous bioactive substances, such as insulin, lactoferrin, proline, and conjugated linoleic acid, that have demonstrated promising effects on wound healing. While direct evidence on skin cell proliferation and migration is limited, the properties of these bioactive substances suggest beneficial effects in these areas. Therefore, incorporating these milks into hydrogel dressings can promote wound healing. Moreover, improving the cell-material mechano-interaction in such hydrogels could lead to the development of novel regenerative medical therapies.
Cells have a mechanism that converts physical forces into biochemical signals, a critical process known as "mechanotransduction." Mechanotransduction plays a vital role in regulating multiple developmental and homeostatic events, including skeletal formation. Although underappreciated for decades, accumulated evidence now suggests that primary cilia play an important role in transducing mechanical stimuli. Since defects in the cilia result in multiple skeletal diseases, the importance of understanding the mechanisms between the mechanotransductive role of the cilia and skeletal health is paramount. However, the cellular mechanism of how cilia function as mechanosensors to control skeletal growth and homeostasis remains unclear. In addition, little is known about whether the manipulation of ciliary signaling related to defective mechanotransduction improves the skeletal disease conditions seen in osteoarthritis and osteoporosis. In this chapter, we provide a comprehensive overview of cilia and their role in mechanotransduction during skeletal development, with a focus on the function of key ciliary genes and intracellular signaling pathways in different skeletal cell types. We also highlight the broad impact of ciliary defects on mechanical stress-related skeletal diseases.
Development of cellular mechanisms to facilitate mechanosensing and mechanotransduction occurred very early in evolution during adaptation to the boundary conditions of Earth, in particular, gravity. Subsequently, with the evolution of increasingly complex organisms leading to Homo sapiens, multiple levels of biological regulatory control of mechanical loading were introduced for connective tissues of the musculoskeletal system. Integration of mechanosensing mechanisms with biological regulatory variables exhibits tissue-specific, lifespan-specific, sex specific features. A key integration component is the regulation of response to ground reaction forces. This chapter will discuss various features of this integration and its dynamic nature across the lifespan, and the critical role of the cell-extracellular matrix relationship, and how sex-specific variables appear to influence the functioning of connective tissues, particularly in females, where lifespan transitions (i.e., puberty, pregnancy and lactation, and menopause) appear to contribute to tissue responses to loading.
Over the past decade, theoretical and experimental work in mechanobiology has become increasingly interdependent, with modeling now serving as an essential tool for interpreting experiments and guiding measurements. Cellular mechanosensation, the conversion of mechanical cues into biochemical signals, governs essential processes such as migration, polarization, lineage specification, and tissue homeostasis, and its dysregulation contributes to disease. Quantitative models of mechanosensation have been central to clarifying how cells detect and respond to force across multiple scales, from ion channels and molecular bonds to adhesions, cytoskeletal dynamics, nuclear deformation, and transcriptional regulators such as YAP/TAZ (Yes-associated protein and transcriptional coactivator with PDZ-binding motif). In this chapter, we survey both experimental and theoretical advances in mechanosensation, emphasizing how mathematical and computational models complement experiments, expose limitations, and generate testable hypotheses and conceptual frameworks.
The myelin sheath is a multilayered glial membrane that surrounds axons providing insulation and rapid propagation of action potentials and contributing to structural support in both the central nervous system (CNS) and the peripheral nervous system (PNS). Therefore, myelin formation plays a crucial role in maintaining the integrity, connectivity, and functionality of the nervous system, as well as neuronal regeneration after injury or damage. Myelination in early developmental stages requires the molecular and mechanical exogenous cues provided mainly by the axons of the neurons, coupling the myelin-generating oligodendrocytes in the CNS and Schwann cells in the PNS. Complementary to early development, adaptive myelination dynamically regulates myelin remodeling in response to neuronal activity, ensuring optimal synaptic function and plasticity. Adaptive myelination is shown to be extremely mechanosensitive, requiring strict spatial constraints, stiffness, and topography for cell plasticity and myelination. Consequently, myelin regeneration is limited after traumatic injury and in demyelinating neurodegenerative diseases such as multiple sclerosis (MS). In addition to the inflammatory niche created around damaged myelin sheath, it is often overlooked that altered mechanical properties of the surrounding tissue are also pivotal in the inhibition of remyelination.This review focuses on the effects of mechanical cues on the polarization and plasticity of myelin generating cells, as well as on the induction of the myelin sheath during normal development and in pathological conditions. It also aims to give insights into potential mechanoepigenetic therapeutic approaches for demyelinating conditions.
The role of, perhaps, the least understood biogenic amine, serotonin, goes beyond transmitting information within the neuroendocrine system. Serotonin has emerged as a critical factor in diverse signaling events across various organs and tissues. In the central nervous system, serotonin, also referred to by its chemical name 5-hydroxytryptamine, regulates behavior, mood, anxiety, sleep, and learning. In the periphery, serotonin signaling is a critical factor in gastrointestinal homeostasis, platelet activation, mammary gland development, lactation, and involution. Various aspects of mammary and gut physiology depend on related functions, where mechanical and biochemical signals converge. In this chapter, we explore some of the overlapping mechanosensory functions modulated by serotonergic signaling that characterize the relatively static mammary gland and the mechanical active gastrointestinal system in their physiologic and disease states.
As a professional mechanosensor, PIEZO1 converts mechanical stimuli-such as substrate stiffness, fluid shear stress, and membrane tension-into intracellular calcium influx, which in turn regulates a wide array of immune processes. The chapter details its significance across both innate and adaptive immunity, including T cell activation and migration, macrophage polarization, dendritic cell activation, natural killer cell cytotoxicity, neutrophil extracellular trap (NET) formation, and B cell antigen discrimination and class-switching to IgA. PIEZO1 emerges as a central regulator that fine-tunes immune responses by integrating signals from the cellular microenvironment, influencing inflammation, pathogen clearance, and metabolic reprogramming. Despite these advances, key questions remain regarding its role in chronic disease, autoimmunity, and cancer immunity. Targeting PIEZO1 presents a promising therapeutic strategy for conditions driven by mechanical stress and immune dysfunction, such as fibrosis, atherosclerosis, and solid tumours, potentially inaugurating a new era of mechano-immunotherapy.
This chapter elucidates the fundamental role of magneto-mechanical stresses as a primary mechanism through which static and low-frequency magnetic fields influence cellular processes. We demonstrate that magnetic forces, particularly when amplified by magnetic nanoparticles (MNPs), exert precise control over cellular mechanics. At the membrane level, these forces induce subtle deformations that directly modulate the gating of mechanosensitive ion channels, such as Piezo1, thereby regulating Ca2+ and K+ fluxes and initiating downstream signaling cascades that govern gene expression, metabolism, and cytoskeletal remodeling. At higher force thresholds, magneto-mechanical stress triggers significant structural alterations, including membrane blebbing due to cortical detachment, which can act as a precursor to apoptosis-an effect with pronounced implications for cancer therapeutics. Furthermore, these magnetic stresses are transmitted through the cytoskeletal network, altering the tension in F-actin, microtubules, and intermediate filaments to remodel cell shape, motility, and adhesion, thereby influencing critical processes like cell migration and differentiation. We demonstrate that the noninvasive and selective nature of this magneto-mechanical approach offers a highly versatile and potent strategy for biomedical applications.
Bone is a highly mechanosensitive tissue that adapts its function in response to mechanical cues. These cues are converted into biomechanical signals that regulate osteogenic gene expression through mechanotransduction. Bone homeostasis and the long-term bone adaptation to its mechanical environment depend on the proper integration of mechanical signals with transcriptional programs that regulate osteogenesis. Runt-related transcription factor 2 (RUNX2) is a pioneer transcription factor, a mechanosensitive molecule, which coordinates osteoblast differentiation and bone remodeling. RUNX2 activity in mechanically induced environments is subject to epigenetic regulation. Mechanical cues modulate RUNX2 through epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs. Proper epigenetic coordination ensures the stability of osteogenic gene expression. Any disruption of this mechanotransduction-epigenetic route leads to bone diseases such as osteoporosis, osteoarthritis, and dysfunctional fracture repair. Moreover, epigenetic reprogramming of RUNX2 is increasingly evident in bone tumors, particularly osteosarcoma, where aberrant RUNX2 activity is associated with cell proliferation, tumor progression, survival, metastasis, and loss of differentiation. This chapter examines current evidence on RUNX2 epigenetic regulation in response to mechanical forces, discusses how its orchestration relates to bone disease and bone tumor development, and underscores potential therapeutic opportunities that arise from targeting specific epigenetic mechanisms.
The TMEM63 family of mechanosensitive ion channels has recently emerged as a distinct group of mammalian force sensors evolutionarily related to plant OSCA channels. Structural and functional studies establish TMEM63s as monomeric, high-threshold mechanotransducers featuring an extended IL2 domain, a hydrophobic latch at the membrane interface, and a lateral lipid-accessible pore that may enable both ion conduction and lipid scrambling. These features define a unique gating mechanism, distinct from other mechanosensitive ion channels. Growing genetic and animal evidence indicates that TMEM63s play diverse and essential roles in the nervous system and other tissues, where altered mechanotransduction can lead to severe neurological and systemic dysfunctions. In this review, we summarize recent progress in the structure, gating mechanisms, and physiological functions of TMEM63 channels, with an emphasis on their force-sensing elements, lipid scrambling activities, and implications in human diseases. We also outline future directions for understanding how TMEM63s convert physical forces into biological signals in health and disease.
