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

描述(申请人提供)：在造血干细胞(HSC)移植后，实现所有造血系的成功植入和再繁殖的第一步是将供者的HSC迁移和归巢到骨髓抑制的受者的骨髓(BM)。HSC归巢经历了一个多步骤的过程，包括循环细胞和内皮细胞之间的直接相互作用，这是由细胞黏附分子介导的。虽然一些黏附分子与HSC归巢过程的不同步骤有关，但黏附分子差异表达的机制以及这如何影响HSC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造血干细胞亚群，它们在稳定状态下表达7整合素。从我们的初步研究中，我们发现当它们与7-HSCs直接竞争时，它们具有多谱系、长期重建受照射宿主的能力，并增加了植入潜能。我们发现，在接受致死性照射的受者中，阻断α4？7整合素配体--粘膜寻址细胞黏附分子-1(MAdCAM1)可阻止移植后长期重建的造血干细胞的植入。因此，我们推测α4？7整合素/MAdCAM1相互作用在供者造血干细胞归巢骨髓抑制的过程中是必不可少的。为了验证这一假设，我们建议：1)确定骨髓抑制后骨髓和脾微环境中MAdCAM-1和7整合素的表达；2)确定7整合素和MAdCAM-1在体内HSCs运输中的作用。该项目的长期目标是定义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.