Mimicking nuclear mechanics in stem cell adhesion on curved rigid substrates using flat soft substrates.

BACKGROUND AND OBJECTIVE: In vitro culture systems are widely used in cell-based research, yet they predominantly rely on flat substrates that fail to capture the curved mechanical landscapes encountered by cells in vivo. While curved substrates offer enhanced physiological relevance, their adoption is often limited by fabrication complexity and cost. Here, we investigate whether flat, soft substrates can reproduce the nuclear stress profiles induced by rigid curved surfaces during cell adhesion. METHODS: Using an axisymmetric finite element model of a human mesenchymal stem cell (hMSC), we show that the nuclear stress states elicited by adhesion to concave geometries can be mimicked by adhesion to flat substrates, provided that substrate stiffness is properly tuned. In contrast, stress patterns associated with convex topographies cannot be reproduced through stiffness modulation, highlighting the dominant mechanobiological role of surface curvature. RESULTS: We derive a nonlinear relationship between the Young's modulus of soft flat substrates and the curvature radius of rigid geometries, providing a predictive framework for the rational design of planar systems that replicate essential aspects of curved mechanotransductive environments. CONCLUSIONS: These findings demonstrate that substrate stiffness can only partially replicate curvature-driven nuclear mechanics, identifying surface curvature as a fundamental and, in some cases, non-replaceable regulator of mechanotransduction, while providing practical guidelines for engineering cost-effective yet physiologically relevant culture systems.