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This study highlights the relevance of optimizing initial cell densities when establishing 3D cultures for specific applications. Independently of the entrapping density, MSCs cultured within RGD\u2010alginate hydrogels showed steady\u2010state levels of metabolic activity and were in a nearly non\u2010proliferative state, but recovered \u201cnormal\u201d activity levels when retrieved from 3D matrices and re\u2010cultured as monolayers. Importantly, high\u2010densities promoted the establishment of cell\u2013cell contacts with formation of multicellular clusters stabilized by endogenous ECM, and also stimulated MSCs osteogenic differentiation. 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