‘Deterministic' Biomaterial Platforms for Directing Stem Cell Fate Choices

Mesenchymal stem cells (MSCs) and pluripotent stem cells (hESC, iPSC) cells, due to their potential to turn into most if not all cell types in our body, represent ideal cell sources for regenerative medicine applications. This presentation will focus on recent outcomes from our lab aimed at elucidating the biophysical properties of a substrate that may be tailored to manipulate MSC (and hESC) fate decisions. Firstly, the complex interplay of substrate ‘rigidity’ and ligand type and availability on MSC fate decisions will be described. We show that substrate stiffness can be completely overridden by ligand-integrin interactions, and that substrate stiffness is not necessarily deterministic of stem cell fate. Secondly, the influence of the ‘creepiness’ of a substrate will be detailed. We have demonstrated that MSCs are explicitly sensitive to variations in the viscous properties of a viscoelastic substrate, not just the elastic properties. The ‘creepier’ the substrate, the more ‘primed’ the cells are for a whole host of fate decisions. More recently, using a Rac1 biosensor, we have shown that this is due to these substrates upregulating Rac1 activity, in contrast to previous studies showing RhoA dominated outcomes. Lastly, the impact of the nano-spatial arrangement of cell adhesion ligands on self assembled functional block copolymer surfaces (changes in lateral spacing of adhesive peptides from ~30 to 60 nm) on MSC fate choice will be described. We demonstrate that the adhesion of MSCs to the block copolymer surfaces is through specific attachment to the presented adhesion motif and with increased lateral spacing of this peptide, we observe significant changes in cell morphology, motility and the ability of MSCs to undergo osteogenesis and adipogenesis - lateral spacing of ligands can be tuned to preference lineage fate choices. We also show that the type of ligand presented to MSCs, at a set lateral spacing, can further specify lineage choice. Each of these ‘deterministic’ biomaterial platforms has provided new insight into permissive cues for differentiation of MSCs, the complexity of intracellular pathways that are regulated by cell-surface interactions and the ultra-sensitivity of stem cells to changes or modulations in their extracellular environment.