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

描述（由申请人提供）：造血干细胞（HSC）移植后，实现所有造血系成功移植和再生的第一步是供体HSC迁移和归巢到骨髓抑制受体的骨髓（BM）中。造血干细胞归巢是一个多步骤的过程，涉及循环细胞和内皮细胞之间的直接相互作用，并由细胞粘附分子介导。尽管一些粘附分子与HSC归巢过程的各个步骤有关，但粘附分子差异表达的机制及其如何影响HSC运输和随后的植入仍然知之甚少。我们最近在BM中发现了一小部分hsc在稳定状态下表达ß7整合素。从我们的初步研究中，我们发现这些ß7+ hsc在与ß7- hsc直接竞争时能够多系、长期重建受照射的宿主，并增加移植潜力。我们发现，在受致死性辐射的受体中，α4ß7整合素配体，粘膜寻址蛋白细胞粘附分子1 （MAdCAM-1）的阻断阻止移植后长期重建hsc的植入。因此，我们假设α4ß7整合素/MAdCAM-1相互作用对于供体造血干细胞向骨髓抑制受体的基底细胞的归巢过程至关重要。为了验证这一假设，我们提出：1)测定骨髓抑制后BM和脾脏微环境中MAdCAM- 1和ß7整合素的表达；2)明确ß7整合素和MAdCAM-1在造血干细胞体内转运中的作用。该项目的长期目标是确定调节造血干细胞归巢的分子相互作用，并阐明这些分子如何影响造血干细胞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 ß7 integrin at steady state. From our preliminary studies, we found that these ß7+ HSCs are capable of multilineage, long-term reconstitution of irradiated hosts and increased engraftment potential when in direct competition with ß7-HSCs. We discovered that blockade of the α4ß7 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 α4ß7 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 ß7 integrin within the BM and spleen microenvironments following myelosuppression; 2) define the function of ß7 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.