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Erythroid/Neutrophil/Basophil) Hematopoietic Progenitor Cell Lines (Self-Renewal/Stem Cells/Differentiation/Bone Marrow/Growth Factors) JOEL S

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Erythroid/Neutrophil/Basophil) Hematopoietic Progenitor Cell Lines (Self-Renewal/Stem Cells/Differentiation/Bone Marrow/Growth Factors) JOEL S Proc. Natl Acad. Sci. USA Vol. 80, pp. 2931-2935, May 1983 Cell Biology Demonstration of permanent factor-dependent multipotential (erythroid/neutrophil/basophil) hematopoietic progenitor cell lines (self-renewal/stem cells/differentiation/bone marrow/growth factors) JOEL S. GREENBERGER*, MARY ANN SAKAKEENY*, R. KEITH HUMPHRIESt, CONNIE J. EAVESt, AND ROBERT J. ECKNER§ *Joint Center for Radiation Therapy, Department of Radiation Therapy, Sidney Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115; tClinical Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20205; tBritish Columbia Cancer Research Institute, Vancouver, British Columbia, V5Z 1L3, Canada; and §Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts 02115 Communicated by Henry S. Kaplan, January 20, 1983 ABSTRACT Multipotential hematopoietic progenitor cell lines tures containing mixed hematopoietic colonies of single-cell or- have been established from nonadherent cell populations re- igin were reported (11). Such colonies contain cells of the moved from continuous mouse bone marrow cultures. Clonal sub- erythroid lineage admixed with megakaryocytes, macrophages, lines of lines B6SUtA or B6JUt derived from single cells formed and in some instances granulocytes, including eosinophils as mixed colonies containing erythroid cells, neutrophil-granulo- well as neutrophils (11-13). We now report the characterization cytes, and basophil/mast cells in semisolid medium containing of permanent lines of factor-dependent and nonmalignant (14, erythropoietin and conditioned medium from pokeweed mitogen- 15) hematopoietic cells that differentiate along erythroid, neu- stimulated spleen cells. Each of several subclones of cell line Ro trophil-granulocyte, and cell after cl formed colonies containing eosinophils, neutrophil-granulo- basophil/mast pathways ap- cytes, and basophil/mast cells in semisolid medium. Multipoten- propriate stimulation in vitro. tiality was maintained in vitro for over 21/2 years. In contrast, cell MATERIALS AND METHODS line 32D formed basophil/mast cell colonies with no detectable differentiation to other pathways. Multipotential cell lines did not Bone Marrow Cultures. Continuous mouse bone marrow produce detectable spleen colonies (CFUs) in vivo, nor did intra- cultures were established according to published procedures, venous inoculation of up to 5 x 107 cells protect lethally irradiated using the contents of a femur and tibia inoculated into 25-cm2 mice from bone marrow failure. Newborn and adult mice inoc- plastic flasks (Corning) in 25% horse serum (Flow Laboratories) ulated with 5 X 107 cells showed no detectable leukemia or solid and 10 ,uM hydrocortisone (16). Cultures were established from tumors after one year. Both multipotential and committed baso- B6.S, C57BL/6JUt, C3H/HeJ, CD-1 Swiss, N:NIH (Swiss), phil/mast cell lines demonstrated absolute dependence upon a and BALB/c mice, medium was changed weekly, and all non- source of a growth factor(s) found in medium conditioned by WEHI- adherent cells were removed (17). Factor-dependent hemato- 3 cells. These cell lines should be of value in studies of the reg- poietic cell lines were derived and grown in McCoy's 5A mod- ulation of hematopoietic stem cell differentiation in vitro. ified medium containing 10% WEHI-3 cell conditioned medium (CM) (18) according to published methods (17). The exact mol- Hematopoietic stem cells, as defined by the spleen colony- ecule or molecules required for growth of these lines is not forming unit (CFUs) assay (1), give rise to a variety of differ- known; however, CM from pokeweed mitogen-stimulated spleen entiated cell types. These may include B and T lymphocytes as cells or the purified fraction of WEHI-3 CM termed interleu- well as erythroid cells, platelets, neutrophilic granulocytes, kin 3 (IL-3) (19) contains the required factor(s). eosinophils, basophil/mast cells, and macrophages. Data sup- Cloning. Briefly, nonadherent cells were harvested from con- porting the common origin of lymphoid and myeloid lineages tinuous mouse bone marrow cultures and were transferred in come primarily from two types of in vivo studies. In the first, 4 ml to 6-cm plastic Falcon Petri dishes and passaged biweekly radiation was used to induce unique chromosomal markers in at 31°C. Cloning was carried out by transfer of serial 1:10 di- donor marrow cells. Such cells were then transplanted into lutions of cells into growth medium containing 0.8% methyl- suitable recipients and subsequently found to have repopulated cellulose. Single-cell-derived colonies at limiting dilution (10- lymphoid as well as myeloid tissues with cells bearing the same 100 cells per ml of culture) were removed by sterile Pasteur marked karyotype (2, 3). The second line of evidence derived pipette on day 7 and then expanded to 107-108 cells. Recloning from the demonstration of the clonal nature of disease states was then carried out on Terasaki microtiter plates (1-10 cells that involve cells of several hematopoietic lineages, including per ml, 1.0 ml per plate) (20). Only cells grown from a single lymphocytes as well as myeloid cells (4, 5). cell progenitor were expanded as cloned lines. The concept of primitive but committed hematopoietic pro- Microscopic, Karyotypic, Histochemical, and Immunologic genitor cells restricted to specific differentiation pathways is Assays. Electron microscopy, histochemical assays for myelo- based on studies using in vitro colony assays. These have shown peroxidase and esterase M (3-hydroxy-2-naphthoic acid 2-meth- that colonies commonly contain cells of a single lineage even oxyanilide chloroacetate substrate), benzidine stain for hemo- though different types of colonies may be present in the same globin, toluidine blue assay for metachromasia, leukocyte al- cultures (6-8) and that these different types of colonies arise kaline phosphatase and lysozyme assays, and Wright/Giemsa from progenitors with different properties (9, 10). In 1977, cul- Abbreviations: CM, conditioned medium; IL-2 and IL-3, interleukins The publication costs ofthis article were defrayed in part by page charge 2 and 3; BFU, burst-forming unit; CFU, colony-forming unit; -e, ery- payment. This article must therefore be hereby marked "advertise- throid; -c, culture; -s, spleen; -meta, metachromatic cells; GM-, gran- ment" in accordance with 18 U.S.C. §1734 solely to indicate this fact. ulocyte/macrophage; G-, granulocyte. 2931 Downloaded by guest on September 30, 2021 2932 Cell Biology: Greenberger et al. Proc. Natl. Acad. Sci. USA 80 (1983) hematologic stain were as reported (21-23). Cells were tested ever, upon stimulation with erythropoietin and CM from poke- for histamine synthesis (22), production of interleukin 2 (IL-2) weed mitogen-stimulated spleen cells as a source of burst-pro- (19) and IL-3 (19), Thyl.2, Lyl, Ly2, and Ly5 antigens and in- moting activity (25), cells with the characteristics of erythroblasts tracellular Ig as described (24). Karyotyping was as reported became apparent (Table 2). (14). Another cell line, Ro cl 3-1, which contained similar numbers Colony-Forming Assays. Colony assays for determination of of metachromasia- and myeloperoxidase-positive cells, also BFUe, CFUe, GM-CFUc, G-CFUc, CFU-meta, and CFUs (by demonstrated properties of eosinophils with detectable lyso- in vivo assay; BFU, burst-forming unit; CFU, colony-forming lecithinase synthesis and light microscopic appearance (Fig. 1). unit; -e, erythroid; -c, culture; GM-, granulocyte/macrophage; Unlike lines B6JUtA cl 7 and B6SUtA cl 27, Ro cl 3-1 failed to G-, granulocyte; -meta, metachromatic cells) were performed show erythropoietic activity when assayed for erythroid colony- according to published procedures (25-27). forming capacity. The single cell origins of lines B6SUtA cl 27, B6JUtA cl 7, RESULTS and Ro cl 3-1 subclone 24, were next meticulously confirmed Factor-dependent cell lines were derived from retrovirus-in- by a further single cell recloning experiment. Ten of 36 sub- fected and uninfected long-term bone marrow cultures of each clones of B6SUtA were, like the original cloned line, able to of several mouse strains (28). As shown in Table 1, cell lines form large erythropoietic colonies in vitro, and subclones of were derived from B6. S (B6SUtA cl 27) and C57BL/6JUt (B6JUt clone 27 continued to form mixed colonies (containing ery- cl 7) as well as from C3H/Hej and CD-1 Swiss mouse strains. throid, neutrophil, and basophil/mast cells) and erythroid These had immature granulated-blast cell morphology, with small (BFUe), neutrophil-granulocyte (GM-CFUc), and basophil/mast numbers of mature neutrophilic granulocytes apparent on cell (CFU-meta) (22) colonies after over 2 years passage in vitro Wright/Giemsa staining. After cloning in methylcellulose, each (Table 3). In the 26 other subclones from the same line, ca- line was recloned by following growth of a single cell in Terasa- pacity for erythroid colony formation was not demonstrable. The ki plates in WEHI-3 CM. Only subclones derived from a single uncloned parent lines B6SUtA and B6JUtA, B6SUtA cl 27 (Ta- cell that was visualized by inverted microscope were expanded ble 3), and each of five single-cell-derived subelones of B6SUtA and carried in vitro for 6 months, then tested in each assay de- cl 27 (Table 3) were assayed at intervals throughout a period of scribed in the methods. several months to test the stability of their mixed erythroid/ As shown in Table 1, cell line B6SUtA cl 27 and B6JUtA cl neutrophil/basophil colony-forming capacity. All remained able 7 demonstrated histochemical properties of cells from at least to form readily detectable mixed macroscopic erythroid/neu- three different hematopoietic pathways. Between 2% and 3% trophil/basophil colonies, and during this period there was also of cells in each of these lines were characterized as mast cell/ no change in expression of granulopoietic differentiation po- basophils with metachromasia positive by toluidine blue, and tential (Table 3). there was detectable histamine in the range of 10-30 ng per 107 A variation was observed in the frequency of mixed colonies cells.
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