<br/>Cardiovascular diseases (CVD) are the leading cause of death in the United States, claiming more lives annually than all cancers combined. One promising approach to combat CVD is to employ healthy patient-derived cells as the therapeutic. As a result, ways to efficiently derive endothelial cells (ECs) from a renewable source of patient-derived human induced pluripotent stem cells (hiPSCs) are needed. Current methods to differentiate ECs from hiPSCs are of low yield, requiring intermediate sorting steps and are difficult to reproduce. Moreover, these methods mainly rely on chemical signals, while mechanical cues have been shown to be essential for initial embryonic development, morphogenic events, and the eventual organization of tissues.<br/>While mechanical regulation of mesenchymal fate has been exhaustively investigated, the role of mechanical cues in the differentiation of hiPSCs towards vascular lineages has been minimally explored. As such, we hypothesized that mechanical regulation of early differentiation events, imposed by either controlling substrate rigidity or extracellular matrix (ECM) availability through micropatterning techniques, could impact downstream lineage specification. We found that priming hiPSCs on physiologically stiff and soft silicone substrates, led to an enhanced mesodermal commitment in comparison to differentiation on traditionally used polystyrene plates. When these primed cells were switched to tissue culture plates and continually differentiated towards vascular linages, we found cells cultured on physiologically stiff and soft regimes during mesoderm induction, robustly differentiated into ECs. In a similar manner, we explored whether mesoderm induction is effected by confinement by limiting ECM availability through differentiating hiPSCs on micropatterned geometries varying in shape and size. Here we found that under geometric confinement, regions of high tension lead to more efficient mesodermal commitment, in comparison to physically un-confined domains. We conclude that the physical and mechanical context of the differentiation niche <i>in </i>vitro biases mesodermal induction, and can be used as an engineered tool for the efficient derivation of vascular lineages from pluripotent cell sources.

Engineering mechanical cues in the stem cell differentiation niche: Applications in vascular tissue engineering

253rd National Meeting (2017)

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