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These include soluble factor signaling with cytokines, cellular confinement in the stem cell niche, and contact\u2010dependent receptor\u2013ligand interactions with stromal cells. Recreating this complex microenvironment in vitro is a principal engineering challenge for regenerative therapies and tissue engineering. While cytokines can be easily supplemented in vitro, and several systems for confined HSC culture have been developed, integrating receptor\u2010based intercellular interactions found in stem cell niches has only been achieved with quantitatively undefined heterotypic co\u2010cultures. We report here the development of microwell\u2010based systems that integrate synthetic cells to mimic receptor\u2013ligand interactions within hematopoietic niches. The synthetic cells are based on droplet\u2010supported lipid bilayers (dsLBs) with cytomimetic stiffness and present Notch receptor ligands on a laterally mobile lipid membrane. We show the system's applicability to individually tune the three signaling axes: soluble factors, confinement, and intercellular interactions for HSC differentiation. 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