Transfusion Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
J Immunol. 2013 Feb 1;190(3):1094-102. doi: 10.4049/jimmunol.1202639. Epub 2012 Dec 21.
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.
祖细胞 B 细胞位于复杂的骨髓 (BM) 微环境中，在那里它们接收生长和成熟的信号。我们之前曾报道过，CXCL12-黏着斑激酶 (FAK)-VLA4 途径在祖细胞 B 细胞黏附和迁移中发挥重要作用。在这项研究中，我们条件性地靶向 B 细胞中的 FAK，发现 B 细胞特异性 FAK 敲除小鼠中祖前 B 细胞、前 B 细胞和未成熟 B 细胞的数量减少了 30-40%。当在含有 IL-7 ± CXCL12 的甲基纤维素中培养时，Fak 缺失的前 B 细胞产生的细胞和集落明显减少。通过原位定量成像细胞计数，我们确定在前股骨 BM 切片中，前 B 细胞优先定位于骺板的骨内膜和骨干附近。Fak 缺失破坏了前 B 细胞的非随机分布，并诱导前 B 细胞在体内向周围迁移。在炎症应激下，即在用硝酸苯肼偶联鸡 γ-球蛋白在明矾中免疫后，Fak 缺失对前 B 细胞动员和 BM 定位的这些影响会放大。总之，这些研究表明 FAK 在调节前 B 细胞稳态和维持其在 BM 龛中的空间分布方面的重要性。
