Anti–VLA4/VCAM-1—Induced Mobilization Requires Cooperative Signaling Through the kit/mkit Ligand Pathway

• Published in: Blood Vol. 91; no. 7; pp. 2231 - 2239
• Main Authors: Papayannopoulou, Thalia, Priestley, Gregory V., Nakamoto, Betty
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.04.1998; The Americain Society of Hematology
• Subjects: Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Biological and medical sciences; Cell Adhesion - drug effects; Cell Adhesion - immunology; Cell differentiation, maturation, development, hematopoiesis; Cell Movement - drug effects; Cell Movement - immunology; Cell physiology; Fundamental and applied biological sciences. Psychology; Hematopoiesis; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - immunology; Integrin alpha4beta1; Integrins - immunology; Mice; Mice, Mutant Strains; Molecular and cellular biology; Proto-Oncogene Proteins c-kit - immunology; Receptors, Lymphocyte Homing - immunology; Signal Transduction - immunology; Stem Cell Factor - immunology; Vascular Cell Adhesion Molecule-1 - immunology; Immunoglobulins; Vascular cell adhesion molecule 1; Stem cell; Cytokine; Rodentia; Cell adhesion molecule; Hematopoietic cell; Mobilization; Cell motility; Signal transduction; Vertebrata; Mammalia; Integrin; Mouse; Hematopoiesis; Animal; C-Onc gene; Protooncogene
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V91.7.2231

Although a large body of data on mobilization have yielded valuable clues, the mechanism(s) dictating egress of stem/progenitor cells during baseline hematopoiesis and after their mobilization are poorly understood. We have previously provided functional in vivo evidence that cytoadhesion molecules, specifically the β1integrins, are involved in mobilization; however, the mechanism by which this was achieved was unclear. To provide further insights into the anti–very late antigen 4 (VLA4)/anti–vascular cell adhesion molecule 1 (VCAM-1)—induced mobilization, we used these antibodies to treat mutant mice with compromised growth factor receptor function. We found that mobilization by anti-VLA4 does not depend on a functional granulocyte colony-stimulating factor, interleukin-7 (IL-7), or IL-3α receptor. By contrast, the functional kit receptor is required, because W/Wv mice responded minimally, whereas Steel-Dickie (Sl/Sld) responded normally. Both Wv and Sl/Sld mice did not respond to anti–VCAM-1 treatment, in contrast to their +/+ littermates and despite normal levels of VCAM-1 expression in bone marrow cells. The defective response to anti–VCAM-1 in W/Wv mice was corrected after their transplantation with +/+ cells. mev/mev mice showed increased numbers of circulating progenitors before treatment and a heightened response after anti-VLA4 or anti–VCAM-1 treatment. Downmodulation of kit expression was detected in normal bone marrow cells after anti-VLA4 treatment. On the strength of the above findings we conclude that (1) anti–VLA4/VCAM-1—induced mobilization likely requires signaling for stimulation of cell migration; (2) this cooperative signaling involves the kit/kit ligand pathway, and provides a novel example of integrin/cytokine crosstalk; and (3) migration mediated through the kit/kit ligand pathway may be a common contributor to different mobilization stimuli. Dissection of the exact molecular pathways that lead to mobilization remains a future challenge.