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However, whether endothelial cell\u2010secreted angiocrine factors have any inductive effects on adult human salivary gland stem\/progenitor cells (hS\/PCs) is unknown. To advance the engineering of functional salivary glands, we probed the effects of epithelial and endothelial crosstalk on the growth and differentiation of hS\/PCs. Culture of hS\/PCs in agarose microwells led to the formation of multicellular spheroids with close cell\u2013cell contacts. Compared with the day 3 culture maintained in the hepatocyte media (HEP) typically used for hS\/PCs, 7\u2010day culture in the endothelial cell growth media (EMG2), significantly increased the expression of genes encoding the E\u2010cadherin (\n                    <jats:italic>CDH1<\/jats:italic>\n                    ), stem\/progenitor markers (\n                    <jats:italic>KRT5<\/jats:italic>\n                    ,\n                    <jats:italic>KRT14<\/jats:italic>\n                    ,\n                    <jats:italic>MYC<\/jats:italic>\n                    ), acinar markers (\n                    <jats:italic>AQP5<\/jats:italic>\n                    ,\n                    <jats:italic>AMY, SLC12A1<\/jats:italic>\n                    ), and extracellular matrix proteins (\n                    <jats:italic>LAMA1<\/jats:italic>\n                    ,\n                    <jats:italic>FN1<\/jats:italic>\n                    ). Subsequent cultivation of hS\/PC spheroids in a hyaluronic acid (HA)\u2010derived, cell\u2010adhesive, and proteolytically degradable hydrogel yielded hydrogel\u2010encapsulated microtissues with complex, multilobulated structures, consisting of fibronectin\u2010encased lobules connected by F\u2010actin structures. Addition of a CD31+\/vWF+ endothelial cell monolayer on top of the hS\/PC\u2010laden gel construct led to the development of salivary gland microtissues containing differentiated cells expressing key acinar and ductal cell markers.\n                    <jats:italic>In vivo<\/jats:italic>\n                    work showed that the cell\u2010free HA gels implanted in the partially resected rat parotid gland were degraded in 21\u2009days and did not adversely affect the native tissue structure. Collectively, fostering epithelial cell\u2013cell interaction and integrating endothelial cell\u2010secreted angiocrine signals led to the development of pro\u2010acinar salivary gland mimetics from adult salivary gland stem\/progenitor cells.\n                  <\/jats:p>","DOI":"10.1002\/btm2.70118","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T05:18:08Z","timestamp":1771478288000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fostering cell\u2013cell interactions and integrating angiocrine factors to promote the development of salivary microtissues in\n                    <scp>3D<\/scp>"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4379-3883","authenticated-orcid":false,"given":"Mugdha","family":"Pol","sequence":"first","affiliation":[{"name":"Department of Biological Sciences University of Delaware  Newark Delaware USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4003-5893","authenticated-orcid":false,"given":"Apoorva S.","family":"Metkari","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering University of Delaware  Newark Delaware USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5558-8418","authenticated-orcid":false,"given":"Stephen M.","family":"Frazier","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering University of Delaware  Newark Delaware USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1436-0192","authenticated-orcid":false,"given":"Joshua B.","family":"Macugay","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering University of Delaware  Newark Delaware USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3096-8460","authenticated-orcid":false,"given":"Hanyuan","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering University of Delaware  Newark Delaware USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1208-6596","authenticated-orcid":false,"given":"Robert L.","family":"Witt","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences University of Delaware  Newark Delaware USA"},{"name":"Helen F. Graham Cancer Center and Research Institute Christiana Care  Newark Delaware USA"},{"name":"Department of Otolaryngology Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Cognetti","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles\u2010Antoine","family":"Assenmacher","sequence":"additional","affiliation":[{"name":"Comparative Pathology Core, School of Veterinary Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3564-5576","authenticated-orcid":false,"given":"Xinqiao","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences University of Delaware  Newark Delaware USA"},{"name":"Department 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