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Blood, 1 October 2004, Vol. 104, No. 7, pp. 2020-2026.
Prepublished online as a Blood First Edition Paper on May 25, 2004; DOI 10.1182/blood-2003-12-4157.


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HEMATOPOIESIS

Integrin {alpha}4{beta}7 and its counterreceptor MAdCAM-1 contribute to hematopoietic progenitor recruitment into bone marrow following transplantation

Yoshio Katayama, Andrés Hidalgo, Anna Peired, and Paul S. Frenette

From the Department of Medicine, Mount Sinai School of Medicine, New York, NY.

Previous studies have shown that {alpha}4{beta}1 (very late activation antigen-4 [VLA-4]) and vascular cell adhesion molecule-1 (VCAM-1) play a major role in hematopoietic progenitor cell (HPC) homing to bone marrow (BM). However, the antibody used to block VLA-4 function in the mouse (hybridoma clone PS/2) is not specific to VLA-4 but inhibits both {alpha}4{beta}1 and {alpha}4{beta}7 integrins. Here we have evaluated the contribution of {alpha}4{beta}7 in HPC homing to BM. LineagenegSca-1posc-kitpos cells from adult mouse BM and the factor-dependent cell progenitor (FDCP)—mix progenitor cell line express similar levels of {alpha}4{beta}7 by flow cytometry. The {alpha}4{beta}7 complex was functional since the chemokine CXCL12 enhanced the adhesion of FDCP-mix to immobilized mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and this was completely abrogated by anti-{alpha}4{beta}7 (hybridoma clone DATK32) or anti-{alpha}4 integrins (PS/2). BM intravital microscopy revealed that {alpha}4{beta}7 plays a predominant role in initial tethering and rolling but not in firm adhesion of FDCP-mix cells. Using homing assays, we demonstrate that {alpha}4{beta}7 on HPCs contributes to about half of all {alpha}4 integrin–mediated homing activity following BM transplantation. MAdCAM-1 is likely expressed since its inhibition significantly reduced HPC homing. Although there may be other {alpha}4{beta}7 integrin ligands involved (eg, fibronectin and VCAM-1), these data thus suggest that {alpha}4{beta}7 and its counterreceptor MAdCAM-1 represent a novel adhesion pathway mediating HPC homing to BM.


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