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When cultured on 2D tissue culture plates, human mesenchymal stem cells (hMSCs) lose their differentiation capacity and clinical potential. Here, we developed a 3D alginate hydrogel functionalized with the Arg\u2010Gly\u2010Asp (RGD) sequence and having mechanical stiffness mimicking the mechanical properties (&lt;5 kPa) of bone marrow. hMSCs cultured in these hydrogels were halted in G\n                    <jats:sub>1<\/jats:sub>\n                    phase of the cell cycle and non\u2010proliferative, as shown by flow cytometry and 5\u2010Ethynyl\u20102'\u2010deoxyuridine (EdU) staining, respectively. Their quiescent state was characterized by an upregulation of enhancer of zeste homolog 1 (EZH1) at the gene level, forkhead box O3 (FoxO3) and cyclin\u2010dependent kinase inhibitor 1B (p27) at the gene and protein levels compared to hMSCs grown in 2D. Studies in 3D hydrogels of collagen or alginate\u2010RGD hydrogels presenting a higher concentration of the peptide revealed that, independently of the concentration of RGD or the chemistry of the adhesion motives, hMSCs cultured in 3D presented a similar phenotype. This phenotype was exclusive to 3D cultures. In 2D, even when cells were serum\u2010deprived and became non\u2010proliferative, the expression of these markers was not observed. We propose that this difference may be the result of mammalian target of rapamycin complex 1 (mTORC1) being downregulated in hMSCs cultured in 3D hydrogels, which induces cells in \u201cdeep\u201d quiescence. Our results represent a step forward towards understanding hMSCs quiescence and its molecular pathways, providing more insight for hMSCs cell therapies.\n                  <\/jats:p>","DOI":"10.1002\/adhm.71001","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T05:34:51Z","timestamp":1773639291000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["3D Soft Hydrogels Induce Human Mesenchymal Stem Cells \u201cDeep\u201d Quiescence"],"prefix":"10.1002","volume":"15","author":[{"given":"David","family":"Boaventura Gomes","sequence":"first","affiliation":[{"name":"Complex Tissue Regeneration Department MERLN Institute for Technology\u2010Inspired Regenerative Medicine Maastricht University  Maastricht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo","family":"Rademakers","sequence":"additional","affiliation":[{"name":"Complex Tissue Regeneration 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