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Stem cell\u2010based bone regenerative approaches emerged as a promising method to resolve bone defects. Microenvironment physical cues, such as the matrix elastic modulus or matrix topography, regulate stem cell differentiation via multiple genes. We constructed gelatin methacryloyl (GelMA), a well\u2010known scaffold, to investigate the impact of elastic modulus on osteogenic differentiation in a three\u2010dimensional environment. Confocal microscope was used to observe and assess the condensates fission and fusion. New bone formation was evaluated by micro\u2010computed tomography at 6\u2009weeks in calvarial defect rat. We found that the light curing increased elastic modulus of GelMA, and the pore size of GelMA decreased. The expression of osteogenic markers was inhibited in hBMSCs cultured in the low\u2010elastic\u2010modulus GelMA. In contrast, the expression of YAP, TAZ and TEAD was increased in the hBMSCs in the low\u2010elastic\u2010modulus GelMA. Furthermore, YAP assembled via liquid\u2013liquid phase separation (LLPS) into condensates that were sensitive to 1\u20326\u2010hexanediol. YAP recruit TAZ and TEAD4, but not RUNX2 into the condensates. In vivo, we also found that hBMSCs in high\u2010elastic\u2010modulus GelMA was more apt to form new bone. This study provides new insight into the mechanism of osteogenic differentiation. Reagents that can regulate the elastic modulus of substrate or LLPS may be applied to promote bone regeneration.<\/jats:p>","DOI":"10.1002\/jbm.a.37590","type":"journal-article","created":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T15:46:37Z","timestamp":1690386397000},"page":"1781-1797","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Elastic modulus of hydrogel regulates osteogenic differentiation via liquid\u2013liquid phase separation of\n                    <scp>YAP<\/scp>"],"prefix":"10.1002","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6889-1108","authenticated-orcid":false,"given":"Kuang","family":"Tan","sequence":"first","affiliation":[{"name":"Department of Orthodontics Peking University School and Hospital of Stomatology  Beijing China"},{"name":"National Center for Stomatology; National Clinical Research Center for Oral Diseases National Engineering Laboratory for Digital 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