Enhancing vascular delivery of stem cells and microparticles

为了使血管输注的干细胞到达靶器官进行修复或使循环肿瘤细胞离开 转移的主要部位，第一步是细胞需要穿过血管壁。 虽然这种轮回确实发生，但确切的机制是难以捉摸的。据推测， 注射的干细胞或循环肿瘤细胞经历类似于白细胞或白色血细胞的过程， 称为渗出。在这个过程中，管腔中的白色血细胞挤压通过内皮屏障， 血管进入周围组织然而，我们的实验室发现， 外渗过程与渗出过程明显不同。我们将这种新的外渗过程命名为 Angiopellosis（“angio”：与血管有关;“pello”：推动，驱逐）。在血管细胞增生过程中， 血管壁经历广泛的重塑，以允许细胞离开管腔，而细胞本身仍然存在。 在活动中明显被动。血管杆菌病支持不符合的群体外渗现象 传统的渗透学说。我们的中心假设是细胞聚集和分子水平的改变 血管炎中涉及的途径可以显著改变细胞外渗的效率，影响细胞的增殖。 干细胞移植的安全性和有效性以及增加对癌细胞转移的理解。我们 初步数据表明粘附分子如整联蛋白和分泌蛋白如基质 金属蛋白酶对血管杆菌病至关重要。在这项研究中，我们计划使用体外血管 模型以及体内斑马鱼和小鼠血管模型，以研究血管炎， 成像技术和一系列的增益和损失的功能实验。目的一是破译 控制注射的干细胞和癌细胞中的血管形成过程。目标2是测试 血管炎激动剂，以改善输注的干细胞植入/功效。目标3是检查 用于心脏损伤中外渗和再生的血管纤维化使能微粒。我们的研究将提供 新的见解细胞外渗和补充目前的孤立渗出理论。统称 提出的机制和翻译实验将提供一个科学的前提，了解细胞 同时提示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.