Integrin alpha4beta7 and its counterreceptor MAdCAM-1 contribute to hematopoietic progenitor recruitment into bone marrow following transplantation.
Previous studies have shown that alpha4beta1 (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 alpha4beta1 and alpha4beta7 integrins. Here we have evaluated the contribution of alpha4beta7 in HPC homing to BM. Lineage(neg)Sca-1(pos)c-kit(pos) cells from adult mouse BM and the factor-dependent cell progenitor (FDCP)-mix progenitor cell line express similar levels of alpha4beta7 by flow cytometry. The alpha4beta7 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-alpha4beta7 (hybridoma clone DATK32) or anti-alpha4 integrins (PS/2). BM intravital microscopy revealed that alpha4beta7 plays a predominant role in initial tethering and rolling but not in firm adhesion of FDCP-mix cells. Using homing assays, we demonstrate that alpha4beta7 on HPCs contributes to about half of all alpha4 integrin-mediated homing activity following BM transplantation. MAdCAM-1 is likely expressed since its inhibition significantly reduced HPC homing. Although there may be other alpha4beta7 integrin ligands involved (eg, fibronectin and VCAM-1), these data thus suggest that alpha4beta7 and its counterreceptor MAdCAM-1 represent a novel adhesion pathway mediating HPC homing to BM.
Katayama
Yoshio
Y
Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Hidalgo
Andrés
A
Peired
Anna
A
Frenette
Paul S
PS
D000818:Animals; D000906:Antibodies / Q000737:chemistry; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules; D002455:Cell Division; D002460:Cell Line; D019070:Cell Lineage; D002478:Cells, Cultured; D019040:E-Selectin / Q000737:chemistry; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D007075:Immunoglobulin M / Q000737:chemistry; D007136:Immunoglobulins / Q000378:metabolism / Q000502:physiology*; D016023:Integrins / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D009088:Mucoproteins / Q000378:metabolism / Q000502:physiology*; D019007:P-Selectin / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013997:Time Factors
D000906:Antibodies; D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D007075:Immunoglobulin M; D007136:Immunoglobulins; D016023:Integrins; D008024:Ligands; C504265:MADCAM1 protein, human; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D019007:P-Selectin; C071777:integrin alpha4beta7