Surface Atomic Structure Directs the Fate of Human Mesenchymal Stem Cells

Stem cells in contact with materials are able to sense their surface features, integrate extracellular matrix (ECM) protein cues through a signal transduction pathway, and ultimately direct cell fate decisions. However, discovering the interdisciplinary mechanisms of how stem cells respond to inherent material surface features still remains a challenge due to the complex, multicomponent signaling milieu present in the ECM environment. Here, we demonstrate that the fate of human mesenchymal stem cells (hMSCs) can be regulated by the inherent physical cue of the material surface down to atomic-scale features. hMSCs on a TiO-terminated SrTiO₃ {110} substrate tend to differentiate into specific lineage cells (osteoblast, chondrocyte, adipocyte), whereas on a TiO₂-terminated SrTiO₃ {100} substrate they are prone to maintain pluripotency. The experimental observations and molecular dynamics simulations indicate that the distinct conformations of the initially adsorbed serum albumin and fibronectin proteins activate the integrin-focal adhesion cytoskeleton actin transduction pathway and, subsequently, direct the gene and protein expressions of hMSCs. Moreover, we demonstrate that the initial protein adsorption behaviors are dependent on the distinct hydroxyl groups originating from different surface atomic structures as well as the work functions. This work, therefore, provides new insights into the fundamental understanding of cell-material interactions and will have a profound impact on further designing materials to direct the stem cell fate.