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* Department of Internal Medicine III, University Hospital, J. W. Goethe University of Frankfurt, Germany;
Institute of Transfusion Medicine, German Red Cross Blood Center, Frankfurt, Germany;
Institute of Pathology, and
|| Department of Hematology/Oncology, University of Regensburg, Germany; and
MainGen Biotechnologie GmbH, Frankfurt, Germany
Correspondence: Dr. Gesine Bug, Medizinische Klinik, Abteilung für Hämatologie und Onkologie, Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. E-mail: G.Bug{at}em.uni-frankfurt.de
Seeding of hematopoietic progenitor cells (HPC) into the bone marrow requires a complex interaction between cell membrane and adhesion systems and cell signaling pathways. We established a multicellular, spheroid coculture model to study HPC migration in a three-dimensional stromal environment. Here, entry of primary CD34+ cells into stroma cell spheroids was independent of the integrins very late antigen (VLA)-4, VLA-5, lymphocyte function-associated antigen-1, and the chemokine receptor CXCR4. Experiments using a panel of bacterial toxins selectively targeting key regulators of cellular locomotion, the Rho family small GTPases Rho, Rac, and Cdc42, revealed a considerable reduction or even abrogation of TF-1 cell migration without an increase of apoptosis or impairment of proliferation. Pertussis toxin, an inhibitor of G
i proteins, showed a similar effect. In some in vitro invasion assays, phosphatidylinositol-3 kinase (PI-3K) was shown to mediate Rac- and Cdc42-induced cell motility and invasion. However, inhibition of the PI-3K pathway by LY294002 did not impair TF-1 cell migration in our three-dimensional model system.
Key Words: very late antigen • lymphocyte function-associated antigen-1 • phosphatidylinositol-3 kinase • pertussis toxin
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