title: IL-7 Dependence in human B lymphopoiesis increases during progression of ontogeny from cord blood to bone marrow.
abstract: IL-7 is critical for B cell production in adult mice; however, its role in human B lymphopoiesis is controversial. One challenge was the inability to differentiate human cord blood (CB) or adult bone marrow (BM) hematopoietic stem cells (HSCs) without murine stroma. Here, we examine the role of IL-7 in human B cell development using a novel, human-only model based on coculturing human HSCs on primary human BM stroma. In this model, IL-7 increases human B cell production by >60-fold from both CB and adult BM HSCs. IL-7-induced increases are dose-dependent and specific to CD19(+) cells. STAT5 phosphorylation and expression of the Ki-67 proliferation Ag indicate that IL-7 acts directly on CD19(+) cells to increase proliferation at the CD34(+) and CD34(-) pro-B cell stages. Without IL-7, HSCs in CB, but not BM, give rise to a small but consistent population of CD19(lo) B lineage cells that express EBF (early B cell factor) and PAX-5 and respond to subsequent IL-7 stimulation. Flt3 ligand, but not thymic stromal-derived lymhopoietin (TSLP), was required for the IL-7-independent production of human B lineage cells. As compared with CB, adult BM shows a reduction of in vitro generative capacity that is progressively more profound in developmentally sequential populations, resulting in an approximately 50-fold reduction in IL-7-dependent B lineage generative capacity. These data provide evidence that IL-7 is essential for human B cell production from adult BM and that IL-7-induced expansion of the pro-B compartment is increasingly critical for human B cell production during the progression of ontogeny.
authors.affiliation: Childrens Hospital Los Angeles, CA 90027, USA.
authors.forename: Yasmin Khan
authors.initials: YK
authors.lastname: Parrish
authors.forename: Ineavely
authors.initials: I
authors.lastname: Baez
authors.forename: Terry-Ann
authors.initials: TA
authors.lastname: Milford
authors.forename: Abigail
authors.initials: A
authors.lastname: Benitez
authors.forename: Nicholas
authors.initials: N
authors.lastname: Galloway
authors.forename: Jaqueline Willeman
authors.initials: JW
authors.lastname: Rogerio
authors.forename: Eva
authors.initials: E
authors.lastname: Sahakian
authors.forename: Mercy
authors.initials: M
authors.lastname: Kagoda
authors.forename: Grace
authors.initials: G
authors.lastname: Huang
authors.forename: Qian-Lin
authors.initials: QL
authors.lastname: Hao
authors.forename: Yazmar
authors.initials: Y
authors.lastname: Sevilla
authors.forename: Lora W
authors.initials: LW
authors.lastname: Barsky
authors.forename: Ewa
authors.initials: E
authors.lastname: Zielinska
authors.forename: Mary A
authors.initials: MA
authors.lastname: Price
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Wall
authors.forename: Sinisa
authors.initials: S
authors.lastname: Dovat
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Payne
mesh_terms: D000328:Adult; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D019070:Cell Lineage / Q000276:immunology; D018920:Coculture Techniques / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay; D005312:Fetal Blood / Q000166:cytology* / Q000276:immunology; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D006801:Humans; D015851:Interleukin-7 / Q000276:immunology* / Q000378:metabolism; D038041:Lymphopoiesis / Q000276:immunology*; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000166:cytology
chemical_list: D015851:Interleukin-7