Role of a4b7 integrin/MAdCAM-1 interaction in hematopoietic stem cell trafficki

描述（由申请人提供）：造血干细胞（HSC）移植后，实现所有造血谱系成功植入和再增殖所需的第一步是供体HSC迁移和归巢至骨髓抑制受体的骨髓（BM）。HSC归巢是一个多步骤的过程，涉及循环细胞和内皮细胞之间由细胞粘附分子介导的直接相互作用。虽然一些粘附分子已被链接到HSC归巢过程的各个步骤，粘附分子的差异表达的机制，以及如何影响HSC的运输和随后的植入仍然知之甚少。我们最近在骨髓中发现了一小部分HSC亚群，它们在稳态时表达β 7整合素。从我们的初步研究中，我们发现这些β 7+ HSC能够在与β 7-HSC直接竞争时进行多谱系，长期重建辐射宿主并增加植入潜力。我们发现，在接受致死剂量照射的受者中，阻断β 7整合素配体，粘膜地址素细胞粘附分子1（MAdCAM-1），阻止了移植后长期重建的HSC的植入。因此，我们推测β 7整合素/MAdCAM-1的相互作用对于供体HSC向骨髓抑制受体BM的归巢过程是必不可少的。为了验证这一假设，我们建议：1）确定骨髓抑制后骨髓和脾脏微环境中MAdCAM- 1和β 7整合素的表达; 2）确定β 7整合素和MAdCAM-1在体内HSC运输中的功能。该项目的长期目标是确定调节HSC归巢的分子相互作用，并阐明这些分子如何影响HSC的运输和随后的植入。

DESCRIPTION (provided by applicant): After hematopoietic stem cell (HSC) transplantation, the first step necessary to attain successful engraftment and repopulation of all hematopoietic lineages is the migration and homing of donor HSCs to the bone marrow (BM) of the myelosuppressed recipient. HSC homing proceeds through a multistep process involving direct interactions between circulating cells and endothelial cells that are mediated by cell adhesion molecules. Although a few adhesion molecules have been linked to various steps of the HSC homing process, the mechanisms underlying the differential expression of adhesion molecules and how this influences HSC trafficking and subsequent engraftment remain poorly understood. We have recently identified a small subpopulation of HSCs in the BM that express �7 integrin at steady state. From our preliminary studies, we found that these �7+ HSCs are capable of multilineage, long-term reconstitution of irradiated hosts and increased engraftment potential when in direct competition with �7-HSCs. We discovered that blockade of the ��7 integrin ligand, mucosal addressin cell adhesion molecule 1 (MAdCAM-1), in lethally irradiated recipients prevented engraftment of long-term reconstituting HSCs after transplantation. Therefore, we hypothesize that the ��7 integrin/MAdCAM-1 interaction is essential for the homing process of donor HSCs to the BM of myelosuppressed recipients. To test this hypothesis, we propose to: 1) determine the expression of MAdCAM- 1 and �7 integrin within the BM and spleen microenvironments following myelosuppression; 2) define the function of �7 integrin and MAdCAM-1 in the trafficking of HSCs in vivo. The long-term goals of this project are to define the molecular interactions that regulate the homing of HSCs and elucidate how these molecules influence HSC trafficking and subsequent engraftment.