Human B Cell Development from Adult Bone Marrow Is Profoundly Dependent on IL-7 Due to Decreased B Lymphoid Generative Capacity.

Abstract

IL-7 is critical for normal murine B cell development, however its role in human B lymphopoiesis is controversial. Here we examine the role of IL-7 in human B cell development using a novel in vitro model based on co-culturing cord blood (CB) and adult bone marrow (BM) hematopoietic stem cells (HSCs) on primary stroma from adult human BM. Addition of IL-7 to this co-culture model increased B cell production by ∼40-fold. IL-7-induced increases were dose-dependent and specific to CD19+ cells. Flow cytometry analysis of STAT5 phosphorylation, and expression of the IL-7Rα and the proliferation antigen, ki-67, indicate that IL-7 acts directly on B cell precursors and that this effect is at least partially mediated through increased proliferation. Ongoing studies are assessing the effects of IL-7 on apoptosis among B cell precursors. IL-7 effects appeared to be most profound in cultures initiated with adult human BM HSCs where few, if any, human B lineage cells are generated in the absence of either mouse or human IL-7 activity. However, when co-cultures initiated with CB and BM HSCs were compared, IL-7-induced increases were similar in magnitude, and B cell precursors responded similarly to IL-7. Therefore we compared CB and BM HSCs with respect to B lymphoid generative capacity. The ability of CB and BM HSCs to generate CD19- progeny in our cultures was not significantly different, however the in vitro B lymphoid generative capacity of adult BM HSCs was 40 times less than that of CB HSCs. Our results provide evidence that IL-7 is critical for B cell production from HSCs in adult BM due to their low B lymphoid generative capacity as compared to HSCs in CB. These studies have implications for B cell recovery following transplantation with stem cells from CB versus BM and suggest that B cell recovery could be impacted by availability of IL-7.