Departments of Pediatrics and Cellular and Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA 92093, USA.
Department of Medicine, Diabetes and Obesity Center of Excellence, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98105, USA.
Cell Rep. 2016 Jan 12;14(2):169-79. doi: 10.1016/j.celrep.2015.12.027. Epub 2015 Dec 31.
During pancreas development, epithelial buds undergo branching morphogenesis to form an exocrine and endocrine gland. Proper morphogenesis is necessary for correct lineage allocation of pancreatic progenitors; however, the cellular events underlying pancreas morphogenesis are unknown. Here, we employed time-lapse microscopy and fluorescent labeling of cells to analyze cell behaviors associated with pancreas morphogenesis. We observed that outer bud cells adjacent to the basement membrane are pleomorphic and rearrange frequently; additionally, they largely remain in the outer cell compartment even after mitosis. These cell behaviors and pancreas branching depend on cell contacts with the basement membrane, which induce actomyosin cytoskeleton remodeling via integrin-mediated activation of FAK/Src signaling. We show that integrin signaling reduces E-cadherin-mediated cell-cell adhesion in outer cells and provide genetic evidence that this regulation is necessary for initiation of branching. Our study suggests that regulation of cell motility and adhesion by local niche cues initiates pancreas branching morphogenesis.
在胰腺发育过程中，上皮芽经历分支形态发生，形成外分泌腺和内分泌腺。适当的形态发生对于胰腺祖细胞的正确谱系分配是必要的；然而，胰腺形态发生的细胞事件尚不清楚。在这里，我们采用延时显微镜和细胞荧光标记来分析与胰腺形态发生相关的细胞行为。我们观察到，靠近基底膜的外芽细胞形态多样，经常重新排列；此外，即使在有丝分裂后，它们也主要保持在外细胞隔室中。这些细胞行为和胰腺分支依赖于与基底膜的细胞接触，这通过整合素介导的 FAK/Src 信号转导诱导肌动球蛋白细胞骨架重塑。我们表明，整合素信号通过整联蛋白介导的 FAK/Src 信号转导减少外细胞中 E-钙粘蛋白介导的细胞-细胞黏附，并提供遗传证据表明，这种调节对于分支的起始是必要的。我们的研究表明，局部生态位线索对细胞迁移和黏附的调节启动了胰腺分支形态发生。
