Analysis of Homing Receptors on Human Adult Stem Cells

人类成体干细胞归巢受体的分析

• 批准号: 7090660
• 负责人: ROBERT SACKSTEIN
• 金额: $ 57.89万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-11 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7090660
• 关键词: CD antigens; bone marrow; cell adhesion; cell adhesion molecules; cell migration; cell population study; clinical research; flow cytometry; genetic strain; hematopoietic stem cells; hemodynamics; human tissue; immunologic receptors; laboratory mouse; receptor expression; shear stress; skin transplantation; stem cells; tissue /cell culture; vascular endothelium; western blottings

DESCRIPTION (provided by applicant): Though many have demonstrated that adult stem cells have broad regenerative capacity in a variety of non-hematopoietic tissues, there is no information available on the molecular mechanism(s) by which adult stem cells migrate to sites other than bone marrow. To exit the vascular compartment, all circulating cells must first bind to the endothelium at the target tissue. The key initial adhesive interactions between cells in blood and endothelium are generally described as "rolling", whereby the fast moving cells in flow begin to "brake" on the endothelial surface. This process is mediated by leukocyte "homing receptors" which consist of molecules specialized for rolling interactions such as L-selectin, PSGL-1, CD44, and the integrins VLA-4, LFA-1 and alpha4beta7. While much is known about the role(s) of these molecules in regulating mature leukocyte trafficking and the migration of human CD34+ hematopoietic progenitor cells into bone marrow, virtually nothing is known about the expression and activity of these molecules as they relate to migration of human adult stem cells to non-hematopoietic sites. We hypothesize that to achieve adequate tissue delivery of infused adult stem cells for regeneration of damaged organs requires that one or more of the homing receptors on adult stem cells be functionally intact and, moreover, that the relative expression/activity of these molecules will determine in part the capacity of the cells to emigrate to relevant non-hematopoietic tissues. In this proposal, we focus our studies on adult stem cells residing in human bone marrow, as this source provides the most accessible and quantitatively greatest amount of adult stem cells for future clinical applications. We aim to define the profile of expression and the functional capabilities of known homing receptors on defined populations of human bone marrow-derived adult stem cells including hematopoietic stem cells (HSCs), mesenchymal stem cells (MSC) and multipotential adult progenitor cells (MAPC). Moreover, to determine whether stem cells express novel homing receptors, we will utilize newly developed technology in our laboratory to examine the full spectrum of membrane molecules that can function as mediators of binding interactions under shear conditions. Based on information derived from these studies, we will analyze human adult stem cell-human endothelial interactions and the migration of human adult stem cells to non-hematopoietic tissue using an in vivo model system of human skin transplanted onto immunodeficient mice. It is anticipated that the results of these studies will guide the development of strategies to achieve high efficiency delivery of human adult stem ceils from the vasculature into target organ(s) for clinical applications of regeneration therapy.

描述（由申请人提供）： 尽管许多人已经证明，成年干细胞在多种非肢体组织中具有广泛的再生能力，但尚无有关成年干细胞迁移到骨髓以外其他部位的分子机制的信息。为了退出血管隔室，所有循环细胞必须首先与目标组织的内皮结合。血液和内皮细胞之间的关键初始粘合剂相互作用通常被描述为“滚动”，从而使流动中的快速移动细胞开始在内皮表面“制动”。该过程是由白细胞“归巢受体”介导的，这些分子由专门用于滚动相互作用的分子组成，例如L-选择素，PSGL-1，CD44和整联蛋白VLA-4，LFA-4，LFA-1和Alpha4beta7。尽管这些分子在调节成熟的白细胞运输以及人CD34+造血祖细胞迁移到骨髓中的迁移中的作用众所周知，但实际上对这些分子的表达和活性几乎一无所知，因为它们与人类成人干细胞向非肿瘤细胞的迁移有关。我们假设，为了实现足够的组织递送注入的成年干细胞以再生受损的器官的再生，要求成人干细胞上的一个或多个归因受体在功能上完好无损，此外，这些分子的相对表达/活性将部分确定细胞的能力，以迁移到相关的非虫质性非虫质组织。在此提案中，我们将研究重点放在居住在人骨髓中的成年干细胞上，因为该来源为将来的临床应用提供了最容易获得和数量最大的成年干细胞。我们旨在定义表达的谱以及已知归因受体在人骨骨髓来源的成年干细胞中的定义种群中的功能能力，包括造血干细胞（HSC），间质干细胞（MSC）和多势成年祖细胞（MAPC）。此外，为了确定干细胞是否表达新型的归巢受体，我们将利用实验室中新开发的技术来检查可以在剪切条件下充当结合相互作用的介体的膜分子的全部光谱。基于这些研究得出的信息，我们将使用移植到免疫缺陷型小鼠的人体皮肤的体内模型系统分析人类成人干细胞 - 人类内皮相互作用，并将人类成人干细胞迁移到非山毛质组织。预计这些研究的结果将指导制定策略，以实现人类成人茎的高效传递，从脉管系统到靶器官，以进行再生治疗的临床应用。