Scarring is a long-lasting problem in higher animals, and reductionist approaches that include studies of stem cells could aid in regenerative treatments. Following our early studies showing homogeneous matrix elasticity can direct stem cell lineages in vitro [Engler et al. Cell 2006], our latest studies involve a new platform wherein copolymerization of collagen I with polyacrylamide produces minimal matrix models of scars (MMMS) in which fractal-fibre bundles segregate heterogeneously to the hydrogel subsurface [Dingal et al. Nature Materials 2015]. Matrix stiffens locally—as in scars—while allowing separate control over adhesive-ligand density. Based on expression analyses of injured mesenchymal tissue, detailed analyses of key pathways focus on scar-like phenotypes of mesenchymal stem cells (MSCs). These cells spread and polarize quickly, increasing nucleoskeletal lamin-A while also slowly up-regulating the ‘scar marker’ smooth muscle actin (SMA). Surprisingly, expression responses to MMMS exhibit less cell-to-cell noise than homogeneously stiff gels. Such differences from bulk-average responses arise because a strong SMA repressor, NKX2.5, slowly exits the nucleus on rigid matrices. NKX2.5 overexpression overrides rigid phenotypes, inhibiting SMA and cell spreading, whereas cytoplasm localized NKX2.5 mutants degrade in well-spread cells. MSCs thus form a ‘mechanical memory’ of rigidity by progressively suppressing NKX2.5, thereby elevating SMA in a scar-like state.