Endothelial Progenitors As Islet Vascular Address

内皮祖细胞作为胰岛血管地址

基本信息

批准号：
7094829
负责人：
LAURA CRISA
金额：
$ 41.83万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2010-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Revascularization of islet transplants has been shown to be supported by blood vessels developing from the host's vasculature surrounding the site of implant. However, recent reports indicate that angiogenesis at sites of injury may also recruit bone marrow-derived endothelial progenitors to the newly forming vessels. We have previously shown that endothelial progenitors circulating in human cord blood can be recruited and mature into endothelial cells at sites of transplant engraftment. Most recently, using bone marrow reconstituted Id1/ld3 deficient mice, a model of bone marrow-derived vasculogenesis, we demonstrated that bone marrow-derived vessels exhibit a highly angiogeneic phenotype in vivo, significantly enhancing engraftment and function of islet transplants, as compared to tissue-derived blood vessels. Furthermore, we show that bone marrow-derived endothelial cells are developmentally and functionally distinct from those derived from pre-existing blood vessels, as they maintain phenotypic hallmarks of early and myeloid hemopoietic precursors and exhibit cytokine and chemokine profiles consistent with limited capabilities to recruit and activate immune cells. Thus, we hypothesize that a biological role of bone marrow-derived endothelial cells is to provide efficient angiogenic functions and "compartimentalize" immune responses at site of healing or tissue engraftment. Our objective is to test this hypothesis by using the Id1ld3-/- mouse model of bone marrow-derived vasculogenesis. In this model, there is a tissue defective angiogenesis that can be rescued by reconstitution with wild type bone marrow, allowing new blood vessels to develop virtually entirely from endothelial progenitors of bone marrow origin. Hence, this model provides a powerful tool to discern the possibly unique functions of the endothelium of hemopoietic origin from those contributed by tissue-derived endothelium and test their relevance to transplant engraftment. Thus, our aims are: 1) To characterize the angiogenic properties of bone marrow-derived vs. tissue-derived endothelium in the engraftment and long-term function of "syngeneic" islet transplants. 2) To define cellular and molecular pathways of leukocyte/endothelial interactions specific to bone marrow and tissue-derived endothelium. 3) To study the functions of bone marrow-derived vasculature in the engraftment of "allogeneic" pancreatic islet transplants, in vivo. This line of studies may help designing novel strategies to control immune responses and improve engraftment at site of transplantation.

描述（由申请人提供）：胰岛移植的血运重建已被证明是由植入部位周围宿主脉管系统发育而来的血管支持的。但是，最近的报道表明，受伤部位的血管生成还可能招募骨髓来源的内皮祖细胞到新形成的血管。我们以前已经表明，可以在移植植入部位招募在人索血液中循环并成熟到内皮细胞中的内皮祖细胞。最近，使用骨髓的ID1/LD3缺乏小鼠，这是一种骨髓衍生的血管生成模型，我们证明了骨髓衍生的血管在体内表现出高度的血管生成型表型，显着增强了与胰岛移植的植入和功能相比，与组织衍生的血管相比，它显着增强了植物和功能。此外，我们表明，骨髓来源的内皮细胞在发育和功能上与源自先前存在的血管的骨骼和功能不同，因为它们维持早期和髓样性血压前体的表型标志，并表现出细胞因子和趋化因子和趋化因子和趋于疾病的能力，可促进免疫和激活细胞。因此，我们假设骨髓衍生的内皮细胞的生物学作用是提供有效的血管生成功能，并在愈合或组织植入部位“分类”免疫反应。我们的目标是通过使用骨髓衍生的血管生成的ID1LD3 - / - 小鼠模型来检验这一假设。在该模型中，有一个组织缺陷的血管生成可以通过用野生型骨髓重建来挽救，从而使新的血管几乎完全从骨髓起源的内皮祖细胞中发展出来。因此，该模型提供了一种强大的工具，可以辨别出由组织来源的内皮贡献的血压起源内皮的独特功能，并测试其与移植植入的相关性。因此，我们的目的是：1）表征骨髓衍生的与组织衍生的内皮在植入和长期的“同步”胰岛移植的长期功能中的血管生成特性。 2）定义白细胞/内皮相互作用的细胞和分子途径，该相互作用特异于骨髓和组织衍生的内皮。 3）研究骨髓衍生的脉管系统在体内植入“同种异体”胰岛移植中的功能。这一研究可能有助于设计新的策略来控制免疫反应并改善移植部位的植入。