Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Amherst, NY 14260-4200, USA.
School of Dentistry, University of Utah, Salt Lake City, Utah 84108, USA.
Acta Biomater. 2020 Mar 15;105:121-130. doi: 10.1016/j.actbio.2020.01.027. Epub 2020 Jan 24.
Previously we developed a fibrin hydrogel (FH) decorated with laminin-111 peptides (L-FH) and supports three-dimensional (3D) gland microstructures containing polarized acinar cells. Here we expand on these results and show that co-culture of rat parotid Par-C10 cells with mesenchymal stem cells produces migrating branches of gland cells into the L1-FH and we identify FGF-7 as the principal morphogenetic signal responsible for branching. On the other hand, another FGF family member and gland morphogen, FGF-10 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 salivary glands that can be used to address developmental questions or as platforms for drug discovery. STATEMENT OF SIGNIFICANCE: Hyposalivation leads to the development of a host of oral diseases. Current treatments only provide temporary relief. Tissue engineering may provide promising permanent solutions. Yet current models are limited to salivary spheroids with no branching networks. Branching structures are vital to an effective functioning gland as they increase the surface area/glandular volume ratio of the tissue, allowing a higher output from the small-sized gland. We describe a strategy that controls branch network formation in salivary glands that is a key in advancing the field of salivary gland tissue engineering.
先前，我们开发了一种带有层粘连蛋白-111 肽（L-FH）的纤维蛋白水凝胶（FH），它支持包含极化腺泡细胞的三维（3D）腺体微结构。在这里，我们扩展了这些结果，并表明大鼠腮腺 Par-C10 细胞与间充质干细胞的共培养会产生腺细胞的迁移分支进入 L1-FH，并且我们确定 FGF-7 是负责分支的主要形态发生信号。另一方面，另一种 FGF 家族成员和腺体形态发生因子 FGF-10 增加了增殖，但没有促进迁移，因此限制了分支结构进入凝胶的数量和长度。通过控制生长因子呈现和传递的方式，我们可以控制分支的长度和细胞密度，以及水凝胶内新节点/簇的形成。这种两种或多种形态发生因子的空间传递可以促进解剖结构复杂的组织/迷你器官的工程设计，例如唾液腺，这些组织可以用于解决发育问题或作为药物发现的平台。 意义声明：唾液过少会导致一系列口腔疾病的发生。目前的治疗方法只能提供暂时的缓解。组织工程可能提供有前途的永久解决方案。然而，目前的模型仅限于没有分支网络的唾液球体。分支结构对于有效的腺体功能至关重要，因为它们增加了组织的表面积/腺体体积比，使小型腺体的产量更高。我们描述了一种控制唾液腺分支网络形成的策略，这是推进唾液腺组织工程领域的关键。
