Enhancing vascular delivery of stem cells and microparticles

为了使注入血管的干细胞到达目标器官进行修复或循环中的肿瘤细胞离开 转移的主要部位，第一步是细胞需要跨血管壁迁移。 虽然这种轮回确实发生了，但确切的机制尚不清楚。据推测， 注射的干细胞或循环中的肿瘤细胞经历类似于白细胞或白细胞的过程， 这就是所谓的渗出现象。在这个过程中，管腔内的白细胞挤过血管内皮细胞屏障。 血管进入周围组织。然而，我们的实验室发现注入的细胞经历了 渗出过程与渗出作用明显不同。我们将这种新的外渗过程命名为 脉络膜病(“angio”：与血管有关；“Pello”：推挤、驱赶)。在脉络膜病的过程中， 血管壁经历广泛的重塑，允许细胞离开管腔，而细胞本身保持不变。 在活动中明显地被动。银屑病支持不适应的群体性外渗现象 传统的渗出理论。我们的中心假设是细胞聚集和分子水平的改变 参与血管病变的通路可以显著改变细胞外渗的效率，影响 干细胞移植的安全性和有效性以及对癌细胞转移的更多了解。我们的 初步数据显示，黏附分子如整合素和分泌蛋白质如基质 金属蛋白酶在血管球蛋白沉着病中起着关键作用。在这项赠款研究中，我们计划使用体外血管 斑马鱼模型和活体斑马鱼和小鼠血管模型来研究血管病变，与最新技术 成像技术和一系列的功能增益和损耗实验。目标1是破译分子 控制注射的干细胞和癌细胞的血管病变过程。目标2是测试 血管球蛋白激动剂，以提高输注的干细胞植入/疗效。目标3是检查潜在的 血管内皮细胞增多症--心脏损伤中用于渗出和再生的微粒。我们的研究将提供 对细胞外渗的新见解和对当前孤立性渗出理论的补充。团结在一起， 提出的机械和平移实验将为理解细胞提供科学前提 外渗，同时建议治疗干预和促进干细胞移植的靶点 技术。

In order for vascularly infused stem cells to reach targeted organ for repair or circulating tumor cells to leave the primary site for metastasis, the first step is that the cells need to transmigrate across the blood vessel wall. Although such transmigration does occur, the exact mechanism is elusive. It has been postulated that the injected stem cells or circulating tumor cells undergo a process similar to leukocytes or white blood cells, termed diapedesis. In this process, white blood cells in the lumen squeeze through the endothelial barrier of the blood vessel into the surrounding tissue. However, our lab has discovered injected cells undergo an extravasation process distinct significantly from diapedesis. We have named this new extravasation process Angiopellosis (“angio”: relating to blood vessels; “pello”: push, drive out). During the angiopellosis process, the vascular wall undergoes extensive remodeling to allow the cell to exit the lumen, while the cell itself remains distinctively passive in activity. Angiopellosis supports the group extravasation phenomenon that does not fit the conventional diapedesis theory. Our central hypothesis is that alterations in cell clustering and molecular pathways involved in angiopellosis can significantly change the efficiency of cell extravasation, impacting the safety and efficacy of stem cell transplantation and increasing understanding of cancer cell metastasis. Our preliminary data suggests adhesion molecules such as integrins and secreted proteins such as matrix metalloproteinases are critical to angiopellosis. In this grant study, we plan to employ in vitro blood vessel models and in vivo zebrafish and mouse models of vasculatures to study angiopellosis, with state-of-art imaging techniques and series of gain- and loss-of-function experiments. AIM 1 is to decipher the molecular control of the angiopellosis process in injected stem cells and cancer cells. AIM 2 is to test the ability of angiopellosis agonists to improve infused stem cell engraftment/efficacy. AIM 3 is to examine the potential of angiopellosis-enabling microparticles for extravasation and regeneration in heart injury. Our study will provide new insights on cell extravasation and complement the current solitary diapedesis theory. Together, the proposed mechanistic and translational experiments will provide a scientific premise to understand cell extravasation while suggesting targets for therapeutic intervention and promoting stem cell transplantation technologies.