Hierarchy of molecular-pathway usage in bone marrow homing and its shift by cytokines.
Efficient bone marrow (BM) homing is a prerequisite for successful engraftment of transplanted hematopoietic cells (HPCs). Contradictory conclusions about the contribution of SDF-1/CXCR4 have clouded our understanding of its role within the molecular pathway cooperation needed for BM homing, particularly with the well-defined hierarchic network of adhesion molecules. In the present study we sought to unravel cooperative and compensatory molecular pathways guiding BM homing. Fresh BM-HPCs, rendered either SDF-1 unresponsive or Gi-signaling refractory, homed quite efficiently, because of compensation by alpha4-integrin interacting with VCAM-1. The contribution of SDF-1/CXCR4- or Gi-protein-mediated signals to BM homing became apparent after their blockade was combined with deletion of alpha4-integrin, leading to dramatic reduction in BM homing. Similar conclusions were revealed when VCAM-1-deficient hosts were used. Cytokine incubation changed the functional properties of BM-HPCs and hierarchy of molecular pathway usage in homing, by shifting the dominance among the homing mediators: loss of CXCR4 or Gi-signaling now significantly reduced BM homing, with only partial compensation through alpha4/VCAM-1 and endothelial selectins. These studies depict a flexible hierarchy of cooperating homing pathways, in which dominant players are repositioned with changing cytokine milieu, and possibly source of HPCs.
Bonig
Halvard
H
Department of Medicine/Hematology, University of Washington, 1959 NE Pacific St, Seattle, WA 98195-7720, USA. hbonig@u.washington.edu
Priestley
Gregory V
GV
Papayannopoulou
Thalia
T
D000818:Animals; D001853:Bone Marrow / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism / Q000502:physiology; D016207:Cytokines / Q000378:metabolism / Q000502:physiology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D039441:Integrin alpha4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D019718:Receptors, CXCR4 / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology
D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D016207:Cytokines; D019718:Receptors, CXCR4; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4; D019206:GTP-Binding Protein alpha Subunits, Gi-Go