Stem cells sense and respond to their local dynamic mechanical niches, which further regulate the cellular behaviors. While in naturally, instead of instantly responding to real-time mechanical changes of their surrounding niches, stem cells often present a delayed cellular response over a time scale, namely cellular mechanical memory, which may finally influence their lineage choice. Here, we aim to build a dynamic mechanical niche model with alginate-based hydrogel, therein the dynamic mechanical switching can be easily realized via the introduce or removal of Ca2+. The results show that stiffening hydrogel (from soft to stiff) suppresses osteogenic differentiation of human mesenchymal stem cells (hMSCs) early on, though it finally promoted osteogenic differentiation over a long time period. Instead, softening hydrogel (from stiff to soft) still retains the strong osteogenic differentiation in the early days, though it finally showed a lower level of osteogenic differentiation compared with stiff hydrogel. Further, microRNA miR-21 has been found as a long-term mechanical memory sensor of the osteogenic program in hMSCs, as its level remains to match early mechanics of substrate over a period of time. Regulation of miR-21 level is efficient to erase the past mechanical memory and resensitize hMSCs to subsequent substrate mechanics. Our findings highlight cellular mechanical memory effect as a key factor of cell and cellular microenvironment interactions, which has been largely neglected before, and as a crucial design element of biomaterials for cell culture.
Keywords: alginate hydrogel; cellular niches; mechanical memory sensor; osteoinduction; tissue engineering.