On a hydrogel substrate with intermediate concentration of biochemical cues, stem cell mechanotransduction depends on substrate stiffness, and increasing substrate stiffness will increase YAP nuclear localization. However, when the concentration of biochemical cues is too low (low ligand) or too high (saturated), biochemical cues will override the effect of substrate stiffness in stem cell mechanotransduction. Regardless of substrate stiffness, low ligand concentration will result in low nuclear YAP whereas high ligand concentration will result in high nuclear YAP.