Engineering the mode of morphogenetic signal presentation to promote branching from salivary gland spheroids in 3D hydrogels
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Xerostomia and Sjӧgren’s Syndrome are conditions associated with loss in salivary volume that is needed to regulate the health of the oral cavity. Current therapies are limited to the introduction of artificial saliva and muscarinic receptor agonists, pilocarpine and cevimeline that induce saliva secretion from residual acinar cells. Regenerative tissue engineering provides a promising platform to solve this problem in the long term by helping rebuild the gland. The salivary tissue is a highly branched network of cells, which enables an increase in surface area without a major increase in glandular volume for high fluid output. Previously we developed a fibrin hydrogel (FH) decorated with laminin-111 peptides (L1p-FH) and supports three-dimensional (3D) gland microstructures containing polarized acinar cells. Here we expand on these results and show that co-culture of gland cells with mesenchymal stem cells produces migrating branches of gland cells into the L1p-FH and we identify FGF7 as the principal morphogenetic signal responsible for branching. On the other hand, another FGF family member and know gland morphogen, FGF10 increased proliferation but did not promote migration and therefore, limited the number and length of branched structures grown into the gel. By controlling the mode of growth factor presentation and delivery, we can control the length and cellularity of branches as well as formation of new nodes/clusters within the hydrogel. Such spatial delivery of two or more morphogens may facilitate engineering of anatomically complex tissues/mini organs such as glands that can be used to address developmental questions or as platforms for drug discovery.