Role of β7 Integrin in Hematopoietic Stem Cell Trafficking.

Abstract 2992

β7 integrin (β7), a well studied integrin chain, associates with either the α4 or αE chains to form a heterodimer on the cell surface. While it plays a key role in the migratory activities of hematopoietic progenitors and mature effector cells in the periphery, the overall importance of β7 in adult hematopoiesis remains controversial. We have recently identified a small subpopulation of hematopoietic stem cells (HSCs) in the bone marrow (BM) that express β7 integrin at steady state. These β7⁺ HSCs are capable of long-term reconstitution of both the lymphoid and myeloid compartments, ruling out the possibility that β7 expression on HSCs constitutes a marker for a homogeneous lineage-restricted progenitor population. We also found that these β7⁺ HSCs have an inherent advantage over β7⁻ HSCs in competitive reconstitution assays. Loss of β7 results in the retention of HSCs in the BM and reduced HSC reconstitution potential. Quantitative real-time PCR revealed that β7 deficient HSCs downregulated the chemokine receptor Cxcr4. Furthermore, blockade of the α4β7 integrin ligand, mucosal addressin cell adhesion molecule 1 (MAdCAM-1), exhibits a similar phenotype in HSC retention and competitive reconstitution. Interestingly, we discovered that β7 deficient mice have enhanced survival and faster hematopoietic recovery after 5-fluorouracil-induced myeloablative stress, indicating that the decreased engraftment of β7 deficient HSCs may not due to a functional defect, but rather is more likely caused by impaired homing capabilities. Taken together, these data strongly suggest that β7 integrin is essential for HSC homing during the transplantation process.