The study shows that lamin-A levels scale with tissue stiffness and influence matrix-directed differentiation. Lamin-A, a nucleoskeletal protein, increases in stiffer tissues and is regulated by the vitamin A/retinoic acid (RA) pathway. Matrix stiffness directly affects lamin-A levels, which in turn stabilize the nucleus and contribute to lineage determination. Tissue stiffness and stress increase lamin-A levels, which stabilize the nucleus while also contributing to lineage determination. The study also shows that matrix stiffness and the presence of specific proteins, such as collagen, influence tissue mechanics and differentiation. Lamin-A and collagen levels scale with tissue microelasticity, with lamin-A increasing 30-fold from soft to stiff tissues. Lamin-A is involved in sensing tissue elasticity during differentiation. The study also shows that lamin-A levels adjust in vivo in response to matrix stiffness, with stiff tissues having higher lamin-A levels. Lamin-A enhances matrix elasticity-directed differentiation, with stiff matrices promoting bone differentiation and soft matrices promoting fat differentiation. The study also shows that lamin-A is regulated by the RA pathway, with lamin-A protein modulating the nuclear entry of RA receptors. The study further shows that lamin-A is involved in mechanosensitive feedback loops that regulate differentiation. The findings suggest that lamin-A is a key factor in tissue mechanics and differentiation, with its levels scaling with tissue stiffness and influencing lineage specification. The study also highlights the importance of lamin-A in nuclear mechanics and its role in mechanoregulating the genome. The results suggest that lamin-A is a critical component of the nuclear lamina, which is involved in sensing tissue elasticity and influencing differentiation. The study provides insights into the molecular mechanisms underlying tissue mechanics and differentiation, with lamin-A playing a central role in these processes.The study shows that lamin-A levels scale with tissue stiffness and influence matrix-directed differentiation. Lamin-A, a nucleoskeletal protein, increases in stiffer tissues and is regulated by the vitamin A/retinoic acid (RA) pathway. Matrix stiffness directly affects lamin-A levels, which in turn stabilize the nucleus and contribute to lineage determination. Tissue stiffness and stress increase lamin-A levels, which stabilize the nucleus while also contributing to lineage determination. The study also shows that matrix stiffness and the presence of specific proteins, such as collagen, influence tissue mechanics and differentiation. Lamin-A and collagen levels scale with tissue microelasticity, with lamin-A increasing 30-fold from soft to stiff tissues. Lamin-A is involved in sensing tissue elasticity during differentiation. The study also shows that lamin-A levels adjust in vivo in response to matrix stiffness, with stiff tissues having higher lamin-A levels. Lamin-A enhances matrix elasticity-directed differentiation, with stiff matrices promoting bone differentiation and soft matrices promoting fat differentiation. The study also shows that lamin-A is regulated by the RA pathway, with lamin-A protein modulating the nuclear entry of RA receptors. The study further shows that lamin-A is involved in mechanosensitive feedback loops that regulate differentiation. The findings suggest that lamin-A is a key factor in tissue mechanics and differentiation, with its levels scaling with tissue stiffness and influencing lineage specification. The study also highlights the importance of lamin-A in nuclear mechanics and its role in mechanoregulating the genome. The results suggest that lamin-A is a critical component of the nuclear lamina, which is involved in sensing tissue elasticity and influencing differentiation. The study provides insights into the molecular mechanisms underlying tissue mechanics and differentiation, with lamin-A playing a central role in these processes.