Differentiation of stem cells, a crucial step in the process of tissue development, repair and
regeneration, can be regulated by a variety of mechanical factors such as the stiffness of extracellular
matrix. In this review article, the effects of stiffness on the differentiation of stem cells, including bone
marrow-derived stem cells, adipose-derived stem cells and neural stem cells, are briefly summarized.
Compared to two-dimensional (2D) surfaces, three-dimensional (3D) hydrogel systems better resemble
the native environment in the body. Hence, the studies which explore the effects of stiffness on stem
cell differentiation in 3D environments are specifically introduced. Integrin is a well-known transmembrane
molecule, which plays an important role in the mechanotransduction process. In this review,
several integrin-associated signaling molecules, including caveolin, piezo and Yes-associated protein
(YAP), are also introduced. In addition, as stiffness-mediated cell differentiation may be affected by
other factors, the combined effects of matrix stiffness and viscoelasticity, surface topography, chemical
composition, and external mechanical stimuli on cell differentiation are also summarized.