Sustained activation of cell adhesion is a differentially regulated process in B lymphopoiesis.
It is largely unknown how hematopoietic progenitors are positioned within specialized niches of the bone marrow microenvironment during development. Chemokines such as CXCL12, previously called stromal cell-derived factor 1, are known to activate cell integrins of circulating leukocytes resulting in transient adhesion before extravasation into tissues. However, this short-term effect does not explain the mechanism by which progenitor cells are retained for prolonged periods in the bone marrow. Here we show that in human bone marrow CXCL12 triggers a sustained adhesion response specifically in progenitor (pro- and pre-) B cells. This sustained adhesion diminishes during B cell maturation in the bone marrow and, strikingly, is absent in circulating mature B cells, which exhibit only transient CXCL12-induced adhesion. The duration of adhesion is tightly correlated with CXCL12-induced activation of focal adhesion kinase (FAK), a known molecule involved in integrin-mediated signaling. Sustained adhesion of progenitor B cells is associated with prolonged FAK activation, whereas transient adhesion in circulating B cells is associated with short-lived FAK activation. Moreover, sustained and transient adhesion responses are differentially affected by pharmacological inhibitors of protein kinase C and phosphatidylinositol 3-kinase. These results provide a developmental cell stage-specific mechanism by which chemokines orchestrate hematopoiesis through sustained rather than transient activation of adhesion and cell survival pathways.
Glodek
Aleksandra M
AM
Joint Program in Transfusion Medicine, Harvard Medical School, Children's Hospital Boston, Boston, MA 02115, USA.
Honczarenko
Marek
M
Le
Yi
Y
Campbell
James J
JJ
Silberstein
Leslie E
LE
D001402:B-Lymphocytes / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology*; D002460:Cell Line; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D006801:Humans; D039041:Integrin alpha4beta1 / Q000502:physiology; D038041:Lymphopoiesis; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D039041:Integrin alpha4beta1; D019010:Vascular Cell Adhesion Molecule-1; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go