title: Focal adhesion kinase regulates the localization and retention of pro-B cells in bone marrow microenvironments.
abstract: Progenitor B cells reside in complex bone marrow (BM) microenvironments where they receive signals for growth and maturation. We reported previously that the CXCL12-focal adhesion kinase (FAK)-VLA4 pathway plays an important role in progenitor B cell adhesion and migration. In this study, we have conditionally targeted in B cells FAK, and found that the numbers of progenitor pro-B, pre-B, and immature B cells are reduced by 30-40% in B cell-specific FAK knockout mice. When cultured in methylcellulose with IL-7 ± CXCL12, Fak-deleted pro-B cells yield significantly fewer cells and colonies. Using in situ quantitative imaging cytometry, we establish that in longitudinal femoral BM sections, pro-B cells are preferentially localized in close proximity to the endosteum of the metaphyses and the diaphysis. Fak deletion disrupts the nonrandom distribution of pro-B cells and induces the mobilization of pro-B cells to the periphery in vivo. These effects of Fak deletion on pro-B cell mobilization and localization in BM are amplified under inflammatory stress, that is, after immunization with nitrophenol-conjugated chicken γ-globulin in alum. Collectively, these studies suggest the importance of FAK in regulating pro-B cell homeostasis and maintenance of their spatial distribution in BM niches.
authors.affiliation: Transfusion Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Shin-Young
authors.initials: SY
authors.lastname: Park
authors.forename: Peter
authors.initials: P
authors.lastname: Wolfram
authors.forename: Kimberly
authors.initials: K
authors.lastname: Canty
authors.forename: Brendan
authors.initials: B
authors.lastname: Harley
authors.forename: César
authors.initials: C
authors.lastname: Nombela-Arrieta
authors.forename: Gregory
authors.initials: G
authors.lastname: Pivarnik
authors.forename: John
authors.initials: J
authors.lastname: Manis
authors.forename: Hilary E
authors.initials: HE
authors.lastname: Beggs
authors.forename: Leslie E
authors.initials: LE
authors.lastname: Silberstein
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology* / Q000637:transplantation; D001853:Bone Marrow / Q000276:immunology / Q000648:ultrastructure*; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D060833:Cellular Microenvironment; D054377:Chemokine CXCL12 / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D003114:Colony-Forming Units Assay; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D006706:Homeostasis; D039041:Integrin alpha4beta1 / Q000502:physiology; D015851:Interleukin-7 / Q000494:pharmacology; D008231:Lymphopenia / Q000209:etiology; D038041:Lymphopoiesis / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D039041:Integrin alpha4beta1; D015851:Interleukin-7; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse