title: Large-scale hematopoietic differentiation of human induced pluripotent stem cells provides granulocytes or macrophages for cell replacement therapies.
abstract: Interleukin-3 (IL-3) is capable of supporting the proliferation of a broad range of hematopoietic cell types, whereas granulocyte colony-stimulating factor (G-CSF) and macrophage CSF (M-CSF) represent critical cytokines in myeloid differentiation. When this was investigated in a pluripotent-stem-cell-based hematopoietic differentiation model, IL-3/G-CSF or IL-3/M-CSF exposure resulted in the continuous generation of myeloid cells from an intermediate myeloid-cell-forming complex containing CD34(+) clonogenic progenitor cells for more than 2 months. Whereas IL-3/G-CSF directed differentiation toward CD45(+)CD11b(+)CD15(+)CD16(+)CD66b(+) granulocytic cells of various differentiation stages up to a segmented morphology displaying the capacity of cytokine-directed migration, respiratory burst response, and neutrophil-extracellular-trap formation, exposure to IL-3/M-CSF resulted in CD45(+)CD11b(+)CD14(+)CD163(+)CD68(+) monocyte/macrophage-type cells capable of phagocytosis and cytokine secretion. Hence, we show here that myeloid specification of human pluripotent stem cells by IL-3/G-CSF or IL-3/M-CSF allows for prolonged and large-scale production of myeloid cells, and thus is suited for cell-fate and disease-modeling studies as well as gene- and cell-therapy applications.
authors: RG Reprogramming and Gene Therapy, REBIRTH Cluster of Excellence, Hannover Medical School, Hannover 30625, Germany; Institute of Experimental Hematology, Hannover Medical School, Hannover 30625, Germany.
authors: Nico
authors: N
authors: Lachmann
authors: RG Reprogramming and Gene Therapy, REBIRTH Cluster of Excellence, Hannover Medical School, Hannover 30625, Germany; Institute of Experimental Hematology, Hannover Medical School, Hannover 30625, Germany.
authors: Mania
authors: M
authors: Ackermann
authors: Department of Respiratory Medicine, Hannover Medical School, Hannover 30625, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover 30625, Germany.
authors: Eileen
authors: E
authors: Frenzel
authors: RG Reprogramming and Gene Therapy, REBIRTH Cluster of Excellence, Hannover Medical School, Hannover 30625, Germany; Institute of Experimental Hematology, Hannover Medical School, Hannover 30625, Germany.
authors: Steffi
authors: S
authors: Liebhaber
authors: RG Reprogramming and Gene Therapy, REBIRTH Cluster of Excellence, Hannover Medical School, Hannover 30625, Germany; Institute of Experimental Hematology, Hannover Medical School, Hannover 30625, Germany.
authors: Sebastian
authors: S
authors: Brennig
authors: Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover 30625, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover 30625, Germany.
authors: Christine
authors: C
authors: Happle
authors: Institute of Experimental Hematology, Hannover Medical School, Hannover 30625, Germany.
authors: Dirk
authors: D
authors: Hoffmann
authors: Department of Molecular Hematopoiesis, Hannover Medical School, Hannover 30625, Germany.
authors: Olga
authors: O
authors: Klimenkova
authors: RG Reprogramming and Gene Therapy, REBIRTH Cluster of Excellence, Hannover Medical School, Hannover 30625, Germany; Institute of Experimental Hematology, Hannover Medical School, Hannover 30625, Germany.
authors: Doreen
authors: D
authors: Lüttge
authors: RG Reprogramming and Gene Therapy, REBIRTH Cluster of Excellence, Hannover Medical School, Hannover 30625, Germany; Institute of Experimental Hematology, Hannover Medical School, Hannover 30625, Germany.
authors: Theresa
authors: T
authors: Buchegger
authors: Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover 30625, Germany.
authors: Mark Philipp
authors: MP
authors: Kühnel
authors: Institute of Experimental Hematology, Hannover Medical School, Hannover 30625, Germany; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Axel
authors: A
authors: Schambach
authors: Department of Respiratory Medicine, Hannover Medical School, Hannover 30625, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover 30625, Germany.
authors: Sabina
authors: S
authors: Janciauskiene
authors: Institute for Transfusion Medicine, Hannover Medical School, Hannover 30625, Germany.
authors: Constanca
authors: C
authors: Figueiredo
authors: Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover 30625, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover 30625, Germany.
authors: Gesine
authors: G
authors: Hansen
authors: Department of Molecular Hematopoiesis, Hannover Medical School, Hannover 30625, Germany.
authors: Julia
authors: J
authors: Skokowa
authors: RG Reprogramming and Gene Therapy, REBIRTH Cluster of Excellence, Hannover Medical School, Hannover 30625, Germany; Institute of Experimental Hematology, Hannover Medical School, Hannover 30625, Germany. Electronic address: moritz.thomas@mh-hannover.de.
authors: Thomas
authors: T
authors: Moritz
mesh_terms: D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006098:Granulocytes / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D007377:Interleukin-3 / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype
chemical_list: D007377:Interleukin-3; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor