Cell adhesion on substrates with variable curvature: Effects on genetic transcription processes

Several studies suggest that changes in nuclear morphology due to forces and deformations as result of cell adhesion on biological substrates can induce molecular streaming through nuclear pore openings and alter chromatin structure. The condensed state of chromatin hinders transcription and replication, while its decompaction, induced by adhesion, plays a key role in differentiation. However, assessing nuclear stress/strain in vivo remains challenging, and the impact of substrate curvature on nuclear mechanics and chromatin structures is still unclear. In this study, we developed an axisymmetric finite element model of a mesenchymal stem cell adhering to substrates with different curvatures to analyze nuclear stress distribution and identify locations where adhesion-induced gene expression may occur. Results reveal a nuclear stress field with principal stresses in radial and circumferential directions, leading to chromatin decondensation and nuclear pore opening. The predicted forces acting on chromatin fibers, estimated and compared with experimental data, remain slightly below 5 pN-the threshold at which internucleosomal attraction is disrupted, triggering chromatin condensation-decondensation transition-. During early spreading, nuclear forces achieved through adhesion on convex substrates approach this threshold more closely than in concave or flat cases. These findings provide insights for tissue engineering and regenerative medicine, where early control of stem cell fate through substrate design is crucial. Understanding how mesenchymal stem cells respond to substrate curvature could lead to improved biomaterial surface topographies for guiding cell behavior. Tailoring curvature and mechanical properties may enhance early lineage commitment, optimizing regenerative strategies for tissue repair and organ regeneration.