The objective of this study was to exploit tissue engineering and microfluidic approaches to fine-tune the cell culture microenvironment in order to mechanically drive differentiation and morphogenetic transformations involved in organoid formation from human iPS cells. We demonstrate that modulating the adhesion microenvironment alone can provide instructive mechanical signatures which influence the pattern of self-assembly and differentiation of stem cells, suggesting that self-assembly and differentiation can be triggered without biochemical interventions. Potentially, this will open up the possibility for organoid generation in vitro based solely on mechanical stimulations, with the benefits of cost reduction, higher controllability and reproducibility.