Tissue cells sense and respond to the stiffness of their substrate, a process critical for development, differentiation, disease, and regeneration. Anchorage-dependent cells require adhesion to a solid substrate for viability, and their behavior is influenced by the mechanical properties of the substrate. Cells on soft substrates exhibit different behaviors compared to those on stiff substrates, with implications for cell growth, differentiation, and function. The stiffness of the extracellular matrix (ECM) is sensed through adhesion complexes and the actin-myosin cytoskeleton, which transmit forces and enable cells to adjust their adhesions, cytoskeleton, and overall state in response to substrate stiffness. The mechanical properties of tissues are determined by their elastic modulus (E), which measures a material's resistance to deformation. Soft tissues like skin, muscle, and brain have varying stiffness, and cells adapt to these differences. For example, epithelial cells and fibroblasts detect and respond to substrate stiffness, with changes in stiffness affecting cell adhesion, cytoskeleton organization, and differentiation. Muscle cells, neurons, and other tissue cells also sense substrate stiffness, which influences their contractility and function. The response of cells to substrate stiffness involves feedback loops that couple to the elasticity of the extracellular environment. Contractile forces generated by actin and myosin filaments are transmitted to the substrate, causing wrinkles or strains in soft gels. Cells adjust their adhesions and cytoskeleton in response to substrate resistance, with implications for cell behavior in different environments. The stiffness of the substrate can also influence cell migration, spreading, and differentiation, with implications for tissue development and regeneration. The mechanical properties of tissues are influenced by factors such as matrix composition, cell type, and environmental conditions. Studies have shown that cells on soft substrates exhibit different behaviors compared to those on stiff substrates, with implications for cell function and tissue mechanics. The ability of cells to sense and respond to substrate stiffness is an active area of research, with implications for understanding disease processes, morphogenesis, and tissue repair. The findings suggest that tissue cells not only adhere to their environment but also actively respond to its mechanical properties, highlighting the importance of mechanosensitivity in cellular behavior.Tissue cells sense and respond to the stiffness of their substrate, a process critical for development, differentiation, disease, and regeneration. Anchorage-dependent cells require adhesion to a solid substrate for viability, and their behavior is influenced by the mechanical properties of the substrate. Cells on soft substrates exhibit different behaviors compared to those on stiff substrates, with implications for cell growth, differentiation, and function. The stiffness of the extracellular matrix (ECM) is sensed through adhesion complexes and the actin-myosin cytoskeleton, which transmit forces and enable cells to adjust their adhesions, cytoskeleton, and overall state in response to substrate stiffness. The mechanical properties of tissues are determined by their elastic modulus (E), which measures a material's resistance to deformation. Soft tissues like skin, muscle, and brain have varying stiffness, and cells adapt to these differences. For example, epithelial cells and fibroblasts detect and respond to substrate stiffness, with changes in stiffness affecting cell adhesion, cytoskeleton organization, and differentiation. Muscle cells, neurons, and other tissue cells also sense substrate stiffness, which influences their contractility and function. The response of cells to substrate stiffness involves feedback loops that couple to the elasticity of the extracellular environment. Contractile forces generated by actin and myosin filaments are transmitted to the substrate, causing wrinkles or strains in soft gels. Cells adjust their adhesions and cytoskeleton in response to substrate resistance, with implications for cell behavior in different environments. The stiffness of the substrate can also influence cell migration, spreading, and differentiation, with implications for tissue development and regeneration. The mechanical properties of tissues are influenced by factors such as matrix composition, cell type, and environmental conditions. Studies have shown that cells on soft substrates exhibit different behaviors compared to those on stiff substrates, with implications for cell function and tissue mechanics. The ability of cells to sense and respond to substrate stiffness is an active area of research, with implications for understanding disease processes, morphogenesis, and tissue repair. The findings suggest that tissue cells not only adhere to their environment but also actively respond to its mechanical properties, highlighting the importance of mechanosensitivity in cellular behavior.