The metastasis-associated 67-kDa laminin receptor is involved in G-CSF-induced hematopoietic stem cell mobilization.
The 67-kDa laminin receptor (67LR) is a nonintegrin cell-surface receptor with high affinity for laminin, which plays a key role in tumor invasion and metastasis. We investigated the role of 67LR in granulocyte colony-stimulating factor (G-CSF)-induced mobilization of CD34+ hematopoietic stem cells (HSCs) from 35 healthy donors. G-CSF-mobilized HSCs, including CD34+/CD38- cells, showed increased 67LR expression as compared with unstimulated marrow HSCs; noteworthy, also, is the fact that the level of 67LR expression in G-CSF-mobilized HSCs correlated significantly with mobilization efficiency. During G-CSF-induced HSC mobilization, the expression of laminin receptors switched from alpha6 integrins, which mediated laminin-dependent adhesion of steady-state human marrow HSCs, to 67LR, responsible for G-CSF-mobilized HSC adhesion and migration toward laminin. In vitro G-CSF treatment, alone or combined with exposure to marrow-derived endothelial cells, induced 67LR up-regulation in marrow HSCs; moreover, anti-67LR antibodies significantly inhibited transendothelial migration of G-CSF-stimulated marrow HSCs. Finally, G-CSF-induced mobilization in mice was associated with 67LR up-regulation both in circulating and marrow CD34+ cells, and anti-67LR antibodies significantly reduced HSC mobilization, providing the first in vivo evidence for 67LR involvement in stem-cell egress from bone marrow after G-CSF administration. In conclusion, 67LR up-regulation in G-CSF-mobilized HSCs correlates with their successful mobilization and reflects its increase in marrow HSCs, which contributes to the egress from bone marrow by mediating laminin-dependent cell adhesion and transendothelial migration.
Selleri
Carmine
C
Department of Biochemistry and Medical Biotechnology, Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council (CNR), Via S Pansini 5, 80131, Naples, Italy.
Ragno
Pia
P
Ricci
Patrizia
P
Visconte
Valeria
V
Scarpato
Nicola
N
Carriero
Maria Vincenza
MV
Rotoli
Bruno
B
Rossi
Guido
G
Montuori
Nunzia
N
D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis; D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D001854:Bone Marrow Cells / Q000378:metabolism; D002448:Cell Adhesion; D004730:Endothelium, Vascular / Q000166:cytology; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D007797:Laminin / Q000737:chemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D017474:Receptors, Laminin / Q000737:chemistry / Q000502:physiology*
D018952:Antigens, CD34; D007797:Laminin; D017474:Receptors, Laminin; D016179:Granulocyte Colony-Stimulating Factor; D051997:ADP-ribosyl Cyclase 1