The main impetus of vascular tissue engineering is clinical translation, but an equally appealing and impactful use of engineered vascular tissues is as preclinical testing platforms for studying vascular disease and developing therapeutic drugs and understanding of physiologically relevant vascular biology. Developing model engineered tissues will aid in narrowing the significant knowledge gaps in functional tissue formation, which is regulated by intricate cell signaling in a three-dimensional space. In this study, we fabricated tubular engineered vascular tissues using cross-linked fibrinogen as a scaffold and nondifferentiated embryonic rat vascular smooth muscle cell line (A10 cells) and mouse embryonic multipotent mesenchymal progenitor cell line (10T1/2 cells) as model vascular cells. Fibrin gel dimensional contraction kinetics study showed that A10 cells embedded in the gel were unable to significantly contract the tissue compared to fibrin-only gels because of their undifferentiated state. In contrast, 10T1/2 cells differentiated with TGF-β1 to a vascular lineage were able to contract the tubular gel significantly owing to the contractile cytoskeletal stress fibers. Because of its vital role in vascular morphogenesis, tissue specification, and maturation, Notch signaling studies in engineered vascular tissues from A10 cells demonstrated cis-inhibition, whereas 10T1/2 cells activated Notch and its downstream targets Hes-1 and the smooth muscle α-actin genes. Taken together, this study showed that (i) contrary to the previously accepted notion, cell-type is important to gel contractions, and (ii) in engineered vascular tissues, Notch signaling is highly context-dependent, where cis-inhibition muted signal activation in A10 vascular cells, whereas Notch was fully activated in 10T1/2 cells. These findings may provide insights to fabricate functional vascular tissues.

中文翻译：

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基于纤维蛋白的工程化血管组织和祖细胞Notch信号的比较研究

血管组织工程的主要推动力是临床翻译，但是对工程化血管组织的同样有吸引力和影响力的使用是临床前测试平台，用于研究血管疾病和开发治疗药物并了解生理相关的血管生物学。开发模型工程组织将有助于缩小功能组织形成中的重要知识缺口，这由三维空间中复杂的细胞信号传导调节。在这项研究中，我们使用交联的纤维蛋白原作为支架和未分化的胚胎大鼠血管平滑肌细胞系（A10细胞）和小鼠胚胎多能间充质祖细胞系（10T1 / 2细胞）作为模型血管细胞，制造了管状工程血管组织。纤维蛋白凝胶的尺寸收缩动力学研究表明，与仅纤维蛋白的凝胶相比，包埋在凝胶中的A10细胞无法显着收缩组织，因为它们处于未分化状态。相反，由于TGF-β1分化为血管谱系的10T1 / 2细胞由于细胞骨架应力纤维的收缩而能够使管状凝胶显着收缩。由于其在血管形态发生，组织规格和成熟中的重要作用，在来自A10细胞的工程化血管组织中的Notch信号研究显示出顺式抑制作用，而10T1 / 2细胞激活了Notch及其下游靶标Hes-1和平滑肌α-肌动蛋白基因。两者合计，这项研究表明（i）与先前公认的概念相反，细胞类型对于凝胶收缩很重要，并且（ii）在工程血管组织中，Notch信号高度依赖于上下文，其中顺式抑制使A10血管细胞中的信号激活静音，而Notch在10T1 / 2细胞中被完全激活。这些发现可能为制造功能性血管组织提供见解。