Encouraging anastomosis of engrafted vascular networks

描述（由申请方提供）：当包埋在胶原凝胶中并植入动物组织时，内皮细胞可形成网络并与宿主血管系统整合。虽然该系统具有很大的临床应用潜力，但它还不够强大。其中一个主要原因是移植的细胞无法通过吻合术与宿主血管连接，对此过程知之甚少。使用纵向活体成像，我们确定了负责连接的机制，并确定了减慢灌注的限速步骤。血管吻合的机制涉及移植细胞包裹现有血管，破坏宿主血管壁和内皮连接重新分配。这一过程允许新生血管“接入”预先存在的网络。拟议的项目将通过专门针对阻碍攻丝的成分来加速这一过程，包括基底膜（Aim 1），宿主周细胞（Aim 2）和宿主内皮细胞（Aim 3）。 公共卫生相关性：虽然这是移植或工程组织存活的重要步骤，但人们对移植物中的血管网络如何与宿主血管连接以实现灌注知之甚少。通过使用活体成像观察这些连接的形成，我们发现植入的血管通过包裹宿主血管并降解它们以窃取血流来连接。在拟议的工作中，我们将利用我们对这一过程的了解来加速移植物的灌注。

DESCRIPTION (provided by applicant): When embedded in collagenous gel and implanted into animal tissue, endothelial cells can form networks and integrate with the host vasculature. Although this system has great potential for clinical applications, it is not yet sufficiently robust. A major reason for this is failure of the engrafted cells to connect with the host blood vessels through anastomosis, and very little is known about this process. Using longitudinal intravital imaging, we identified the mechanism responsible for the connections, and determined the rate-limiting step that slows the perfusion. The mechanism of vessel anastomosis involves wrapping of existing vessels by the engrafted cells, disruption of the host vessel wall and endothelial junction reassignment. The process allows the nascent vessels to "tap" into the pre-existing network. The proposed project will accelerate this process by specifically targeting components that hinder tapping, including basement membrane (Aim 1), host pericytes (Aim 2) and host endothelium (Aim 3). PUBLIC HEALTH RELEVANCE: Although it's an essential step for survival of transplanted or engineered tissue, very little is known about how blood vessel networks in the graft connect with host vessels to achieve perfusion. By observing the formation of these connections using intravital imaging, we found that the implanted vessels connect by wrapping around host vessels and degrading them to steal the blood flow. In the proposed work we will take advantage of our knowledge of this process to accelerate perfusion of grafts.