Two-Way Regulation of MgFe-LDH on ESC Cell Fate via Temporal Selective Activation of Different Cell Membrane Receptors

Stem cell fate regulation by biomaterials has considerable therapeutic potential; however, the mechanisms whereby biomaterials instruct stem cells for accurate fate regulation still need to be elucidated. Layered double hydroxide (LDH) nanoparticles are widely used for tissue regeneration because of their excellent physicochemical properties and biocompatibility. This study reveals that MgFe-LDH has bidirectional regulatory effects on the differentiation of mouse embryonic stem cells into neural progenitor cells, essentially suppressing cell differentiation on the 1st day and promoting cell differentiation on the 3rd day. Single-cell transcriptome sequencing and simulated computation of structural analysis demonstrate that MgFe-LDH interacts with the membrane receptors leukemia inhibitory factor receptor (LIFR, 15 nm above the cell membrane) and pached1 (PTCH1, 6 nm above the cell membrane) on the 1st and 3rd day of differentiation, respectively. LIFR has more contact with MgFe-LDH than PTCH1 and relatively weaker electrostatic interaction energies (-11010.0 and -9829.3 kJ mol-1 for PTCH1 and LIFR, respectively). These factors determine receptor binding and activation priority, followed by cell fate regulation. The results indicate that MgFe-LDH regulate the activity and fate of stem cells dually, thus creating possibilities for personalized therapy in neurodevelopment and regenerative medicine through an in-depth study of cell membrane receptors. To address the paucity of studies into the mechanisms of cell-instructive nanomaterials, single-cell and RNA sequencing, as well as molecular dynamic simulations are used to elucidate the mechanism whereby nanoparticulate MgFe layer double hydroxides (LDH) can either promote the self-renewal or neurogenic differentiation of embryonic stem cells in a time-dependent manner by specific cell membrane receptors (LIFR and PTCH1) activation. image