Colocalization of islets with immunoprivileged cell types such as mesenchymal stromal cells (MSCs) is a potentially multifaceted and adaptive approach to islet protection. We attempted to colocalize MSCs with islets by creating single-celled suspensions of MSCs and cells from dissociated islets on top of arrays of round-bottomed wells. Segregation between islet-derived cells and MSCs was observed within 3 days. When ROCK inhibitor Y-27632-containing medium was used during the preparation of MSC/islet coaggregates, coaggregates sorted into core-shell structures with islet-derived cells occupying the exterior while MSCs occupied the core. Immunostaining revealed that MSC-derived regions transition from expression of N-cadherin, vimentin, and CD44 to expression of E-cadherin, while pan-cadherin staining indicated reallocation of cadherins to cell borders, and shear-based cohesion measurements pointed to increased cohesive strength. The switch suggests that MSC-islet cohesion improved due to the greater degree of cell-cell adhesive compatibility. Functional evaluation of MSC-islet coaggregates confirmed normal insulin secretory function and partial suppression of anti-CD3-activated splenocyte proliferation. These findings demonstrate that manipulation of cell-cell interactions can be harnessed to control spheroid architecture in MSC-islet coaggregates, and this study also provides the basis for future islet therapies.