Synergistic Effect of Matrix Stiffness and Inflammatory Factors on Osteogenic Differentiation of MSC

Mesenchymal stem cells (MSCs) in vivo reside in a complex microenvironment. Changes of both biochemical and biophysical cues in the microenvironment caused by inflammation affect the differentiation behaviors of MSCs. Most studies, however, only focus on either biochemical or biophysical cues, although the synergistic effect of matrix stiffness and inflammatory factors on osteogenic differentiation of MSCs has not been explored yet. Here, we showed that there was a matrix stiffness-dependent modulation in the osteogenic differentiation of human MSCs (hMSCs) with higher matrix stiffness favoring osteogenesis bias. However, when interleukin-1 β (IL-1β) was added, the osteogenic differentiation of hMSCs was suppressed, which was independent of increasing matrix stiffness. Both experimental observations and mathematical modeling confirmed that matrix stiffness and IL-1β could activate the ERK1/2 signaling and contribute to osteogenic differentiation. The p38 signaling activated by IL-1β has a strong role in inhibiting osteoblastic differentiation, thus diminishing the vital effect of ERK1/2 signaling. In addition, sensitivity analysis of the model parameters revealed that activation/deactivation dynamics of sensitive factors (e.g., FAK, ERK, and p38) also played a key role in the synergistic effect of matrix stiffness and IL-1β on the osteogenic differentiation of hMSCs. The outcomes of this study provide new insights into the synergistic effect of biochemical and biophysical microenvironments on regulating MSC differentiation.