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.
The fundamental knowledge gained from these studies can be applied towards novel therapeutic strategies to control the fate of circulating HSCs, and thus enhance the homing and subsequent engraftment of donor HSCs after transplantation. Ultimately, this will enable the use of fewer HSCs in clinical protocols, thereby allowing more patients to benefit from a single BM donor.