 Mechanical signals from the extracellular matrix stiffness play an important role in regulating the proliferation and differentiation of bone marrow mesenchymal stem cells, BMSEs, for tissue engineering purposes. The incorporation of BMSEs into soft hydrogels limits their ability to differentiate into osteoblasts, while mechanical stimulation can enhance their differentiation into osteoblasts. We have identified a microRNA, MIR-99B, which regulates the proliferation and differentiation of BMSEs in response to varying levels of matrix stiffness. This microRNA also promotes the migration of BMSEs in three-dimensional hydrogels. Additionally, MIR-99B can be used to modulate the osteogenic differentiation of BMSEs in soft hydrogels. Overall, this study demonstrates how mechanical signals from the extracellular matrix stiffness can be used to control the proliferation and differentiation of BMSEs for tissue engineering purposes. This article was authored by Bo Jun Chao, Justin Lee, Xiao Wen Wang, and others. We are article.tv, links in the description below.