FAK Regulates Progenitor B Cell Growth, Localization and Retention in Bone Marrow Microenvironments

Progenitor B cells are thought to reside in complex bone marrow microenvironments, e.g. niches, where they receive signals for growth and maturation. Here we have conditionally targeted in B cells the non-receptor tyrosine kinase, Focal Adhesion Kinase (FAK), because of its function as an integrator of cell extrinsic signals including CXCL12 and VCAM-1. The number of progenitor (pro-, pre- and immature) B cells is reduced by 30–40% in CD19-Cre Fak fl/fl mice compared to wild type mice, and ex vivo cultured, Fak deleted pro-B cells exhibit impaired IL-7 ± CXCL12 mediated proliferation and survival. A novel quantitative laser scanning cytometry approach was used to demonstrate that Fak deletion also disrupts the non-random gradient distribution in femoral bone marrow of progenitor B cells, which normally are preferentially localized in endosteal regions of the metaphyses and to a lesser degree of the diaphysis. Increased numbers of pro-B cells are detected in the periphery of Fak deleted mice, and mobilization of pro-B cells induced by the inflammatory antigen NP-CGG-alum is increased 3-fold in Fak-deleted versus wild type mice. In addition, intravenously transferred Fak deleted pro-B cells have defective homing specifically to the extra-vascular compartment of the bone marrow. Collectively, these studies illustrate the importance of FAK in regulating progenitor B cell homeostasis and maintenance of their spatial distribution in bone marrow niches.