title: Single adult human CD34(+)/Lin-/CD38(-) progenitors give rise to natural killer cells, B-lineage cells, dendritic cells, and myeloid cells.
abstract: Marrow stromal cultures support adult CD34(+)/Lin-/HLA-DR- or CD34(+)/Lin-/CD38(-) cell differentiation into natural killer (NK) or myeloid cells, but unlike committed lymphoid progenitors (CD34(+)/Lin-/CD45RA+/CD10(+)), no B cells are generated. We tested whether different microenvironments could establish a developmental link between the NK and B-cell lineages. Progenitors were cultured in limiting dilutions with interleukin-7 (IL-7), flt3 ligand (FL), c-kit ligand (KL), IL-3, IL-2, and AFT024, a murine fetal liver line, which supports culture of transplantable murine stem cells. NK cells, CD10(+)/CD19(+) B-lineage cells and dendritic cells (DC) developed from the same starting population and IL-7, FL, and KL were required in this process. Single cell deposition of 3,872 CD34(+)/Lin-/CD38(-) cells onto AFT024 with IL-7, FL, KL, IL-2, and IL-3 showed that a one time addition of IL-3 at culture initiation was essential for multilineage differentiation from single cells. Single and double lineage progeny were frequently detected, but more importantly, 2% of single cells could give rise to at least three lineages (NK cells, B-lineage cells, and DC or myeloid cells) providing direct evidence that NK and B-lineage differentiation derive from a common lymphomyeloid hematopoietic progenitor under the same conditions. This study provides new insights into the role of the microenvironment niche, which governs the earliest events in lymphoid development.
authors.affiliation: Department of Medicine, University of Minnesota Cancer Center, Minneapolis, MN 55455, USA. mille011@tc.umn.edu
authors.forename: J S
authors.initials: JS
authors.lastname: Miller
authors.forename: V
authors.initials: V
authors.lastname: McCullar
authors.forename: M
authors.initials: M
authors.lastname: Punzel
authors.forename: I R
authors.initials: IR
authors.lastname: Lemischka
authors.forename: K A
authors.initials: KA
authors.lastname: Moore
mesh_terms: D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000328:Adult; D000818:Animals; D015703:Antigens, CD; D018952:Antigens, CD34 / Q000032:analysis / Q000096:biosynthesis; D000943:Antigens, Differentiation / Q000032:analysis; D001402:B-Lymphocytes / Q000166:cytology*; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D002461:Cell Line, Transformed; D019070:Cell Lineage / Q000276:immunology; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology*; D008562:Membrane Glycoproteins; D051379:Mice; D009244:NAD+ Nucleosidase / Q000032:analysis; D017154:Stromal Cells / Q000166:cytology
chemical_list: D015703:Antigens, CD; D018952:Antigens, CD34; D000943:Antigens, Differentiation; D008562:Membrane Glycoproteins; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; C498155:Cd38 protein, mouse; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1