The study investigates the relationship between tissue mechanics and differentiation, focusing on the role of nuclear lamins, specifically lamin-A. Proteomics analyses revealed that lamin-A levels scaled with tissue elasticity, similar to collagen levels in the extracellular matrix. Stem cell differentiation into fat on soft matrices was enhanced by low lamin-A levels, while differentiation into bone on stiff matrices was enhanced by high lamin-A levels. Matrix stiffness directly influenced lamin-A protein levels, and RA receptors' nuclear entry was modulated by lamin-A. Tissue stiffness and stress increased lamin-A levels, which stabilized the nucleus and contributed to lineage determination. The study also explored the mechanosensitive conformation and abundance of lamin-A in cultured cells, and its impact on differentiation. Lamin-A enhanced matrix elasticity-directed differentiation, and high lamin-A levels impeded nuclear remodeling under stress. The findings suggest that lamin-A is a key factor in regulating lineage specification and maintaining nuclear stability in response to tissue mechanics.The study investigates the relationship between tissue mechanics and differentiation, focusing on the role of nuclear lamins, specifically lamin-A. Proteomics analyses revealed that lamin-A levels scaled with tissue elasticity, similar to collagen levels in the extracellular matrix. Stem cell differentiation into fat on soft matrices was enhanced by low lamin-A levels, while differentiation into bone on stiff matrices was enhanced by high lamin-A levels. Matrix stiffness directly influenced lamin-A protein levels, and RA receptors' nuclear entry was modulated by lamin-A. Tissue stiffness and stress increased lamin-A levels, which stabilized the nucleus and contributed to lineage determination. The study also explored the mechanosensitive conformation and abundance of lamin-A in cultured cells, and its impact on differentiation. Lamin-A enhanced matrix elasticity-directed differentiation, and high lamin-A levels impeded nuclear remodeling under stress. The findings suggest that lamin-A is a key factor in regulating lineage specification and maintaining nuclear stability in response to tissue mechanics.