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：
8002514
负责人：
LAURA CRISA
金额：
$ 26.05万
依托单位：
UNIVERSITY OF WASHINGTON
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 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8002514
关键词：
Address Affect Allogenic Antigens Biological Blood Vessels Bone Marrow Cell Transplants Cells Chimera organism Development Effector Cell Endothelial Cells Endothelium Engraftment Exhibits Genes Graft Survival Healed Heterogeneity Human Immune Immune Cell Activation Immune response Implant In Vitro Injury Islets of Langerhans Leukocytes Mediator of activation protein Modeling Molecular Mus Myelogenous Nutrient Pathway interactions Phenotype Population Property Recruitment Activity Reporting Research Personnel Role SCID Mice Screening procedure Site Testing Tissue Grafts Tissues Transplantation Transplanted tissue Umbilical Cord Blood Vascular Endothelium Vascularization angiogenesis chemokine cytokine design healing improved in vivo islet leukocyte homing migration mouse model novel strategies progenitor programs receptor reconstitution research study tool trait tumor vascular bed vasculogenesis

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）：胰岛移植物的血运重建已被证明受到植入部位周围宿主脉管系统发育的血管的支持。然而，最近的报告表明，损伤部位的血管生成也可能将骨髓来源的内皮祖细胞募集到新形成的血管中。我们之前已经证明，人类脐带血中循环的内皮祖细胞可以在移植物植入部位被募集并成熟为内皮细胞。最近，使用骨髓重建的 Id1/ld3 缺陷小鼠（一种骨髓源性血管发生模型），我们证明骨髓源性血管在体内表现出高度血管生成表型，与胰岛移植相比，显着增强了胰岛移植的植入和功能。组织来源的血管。此外，我们发现骨髓来源的内皮细胞在发育和功能上与那些源自预先存在的血管的内皮细胞不同，因为它们保持早期和骨髓造血前体的表型特征，并表现出与有限的招募和趋化能力一致的细胞因子和趋化因子谱。激活免疫细胞。因此，我们假设骨髓来源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移植部位“划分”免疫反应。我们的目标是通过使用 Id1ld3-/- 小鼠骨髓源性血管生成模型来检验这一假设。在该模型中，存在组织缺陷性血管生成，可以通过用野生型骨髓重建来挽救，从而使新血管几乎完全由骨髓来源的内皮祖细胞发育而来。因此，该模型提供了一个强大的工具，可以区分造血起源的内皮细胞可能具有的独特功能与组织源性内皮细胞所贡献的功能，并测试它们与移植物植入的相关性。因此，我们的目标是： 1) 表征骨髓源性内皮与组织源性内皮在“同基因”胰岛移植的植入和长期功能中的血管生成特性。 2) 定义特定于骨髓和组织源性内皮的白细胞/内皮相互作用的细胞和分子途径。 3) 研究骨髓源性脉管系统在体内“同种异体”胰岛移植物植入中的功能。这一系列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。