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

Beckman Research Institute/City Of Hope, Duarte CA

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Abstract

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 ?4ß7 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 ?4ß7 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.