Fostering cell–cell interactions and integrating angiocrine factors to promote the development of salivary microtissues in 3D

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Author(s)Pol, Mugdha
Author(s)Metkari, Apoorva S.
Author(s)Frazier, Stephen M.
Author(s)Macugay, Joshua B.
Author(s)Gao, Hanyuan
Author(s)Witt, Robert L.
Author(s)Cognetti, David M.
Author(s)Assenmacher, Charles-Antoine
Author(s)Jia, Xinqiao
Date Accessioned2026-02-27T20:25:47Z
Date Available2026-02-27T20:25:47Z
Publication Date2026-02-18
DescriptionThis article was originally published in Bioengineering and Translational Medicine. The version of record is available at: https://doi.org/10.1002/btm2.70118 This is an open access article under the terms of the Creative Commons Attribution License, https://creativecommons.org/licenses/by/4.0/ which permits use, distribution and reproduction in any medium,provided the original work is properly cited. © 2026 The Author(s). Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.
AbstractSalivary gland development requires vascular input signals. However, whether endothelial cell-secreted 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–cell contacts. Compared with the day 3 culture maintained in the hepatocyte media (HEP) typically used for hS/PCs, 7-day culture in the endothelial cell growth media (EMG2), significantly increased the expression of genes encoding the E-cadherin (CDH1), stem/progenitor markers (KRT5, KRT14, MYC), acinar markers (AQP5, AMY, SLC12A1), and extracellular matrix proteins (LAMA1, FN1). Subsequent cultivation of hS/PC spheroids in a hyaluronic acid (HA)-derived, cell-adhesive, and proteolytically degradable hydrogel yielded hydrogel-encapsulated microtissues with complex, multilobulated structures, consisting of fibronectin-encased lobules connected by F-actin structures. Addition of a CD31+/vWF+ endothelial cell monolayer on top of the hS/PC-laden gel construct led to the development of salivary gland microtissues containing differentiated cells expressing key acinar and ductal cell markers. In vivo work showed that the cell-free HA gels implanted in the partially resected rat parotid gland were degraded in 21 days and did not adversely affect the native tissue structure. Collectively, fostering epithelial cell–cell interaction and integrating endothelial cell-secreted angiocrine signals led to the development of pro-acinar salivary gland mimetics from adult salivary gland stem/progenitor cells.
SponsorThis work was supported in part by the National Institutes of Health (NIDCR R01 DE029655, NIDCD, R01DC014461) and the National Science Foundation (NSF, DMR 2243648). The authors also acknowledge the use of facilities and instrumentation supported by NSF through the University of Delaware Materials Research Science and Engineering Center (DMR 2011824). Microscopy access was supported by grants from the NIH-NIGMS (P20 GM103446), the NSF (IIA-1301765), and the State of Delaware. This research also benefited from the BioStore data management resource at the University of Delaware Bioinformatics Data Science Core (RRID: SCR_017696), supported by an NIH shared instrumentation grant (NIH S10 OD028725) and the Delaware INBRE (P20 GM103446). We thank Drs. Jeff Caplan, Sylvain le Marchand, and Chandran Sabanayagam for their guidance on confocal imaging and image analysis. We also thank Genzyme-Sanofi for generously providing HA. We thank the technicians at the CPC's histology lab for their technical support. The veterinary pathologist performing the histopathological analysis is part of the University of Pennsylvania Penn Vet Comparative Pathology Core Facility (RRID:SCR_022438) and is supported by the Abramson Cancer Center Support Grant (P30 CA016520).
CitationPol M, Metkari AS, Frazier SM, et al. Fostering cell–cell interactions and integrating angiocrine factors to promote the development of salivary microtissues in 3D. Bioeng Transl Med. 2026;e70118. https://doi.org/10.1002/btm2.70118
ISSN2380-6761
URLhttps://udspace.udel.edu/handle/19716/36941
Languageen_US
PublisherBioengineering and Translational Medicine
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
Keywordsangiocrine factors
Keywordscell–cell interactions
Keywordsendothelial cells
Keywordshydrogels
Keywordsmicrotissues
Keywordssalivary gland stem/progenitor cells
TitleFostering cell–cell interactions and integrating angiocrine factors to promote the development of salivary microtissues in 3D
TypeArticle
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