Mechanics-Controlled Dynamic Cell Niches Guided Osteogenic Differentiation of Stem Cells via Preserved Cellular Mechanical Memory

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.