title: Inability of human induced pluripotent stem cell-hematopoietic derivatives to downregulate microRNAs in vivo reveals a block in xenograft hematopoietic regeneration.
abstract: Hematopoietic stem cells (HSCs) can regenerate the entire hematopoietic system in vivo, providing the most relevant criteria to measure candidate HSCs derived from human embryonic stem cell (hESC) or induced pluripotent stem cell (hiPSC) sources. Here we show that, unlike primitive hematopoietic cells derived from hESCs, phenotypically identical cells derived from hiPSC are more permissive to graft the bone marrow of xenotransplantation recipients. Despite establishment of bone marrow graft, hiPSC-derived cells fail to demonstrate hematopoietic differentiation in vivo. However, once removed from recipient bone marrow, hiPSC-derived grafts were capable of in vitro multilineage hematopoietic differentiation, indicating that xenograft imparts a restriction to in vivo hematopoietic progression. This failure to regenerate multilineage hematopoiesis in vivo was attributed to the inability to downregulate key microRNAs involved in hematopoiesis. Based on these analyses, our study indicates that hiPSCs provide a beneficial source of pluripotent stem cell-derived hematopoietic cells for transplantation compared with hESCs. Since use of the human-mouse xenograft models prevents detection of putative hiPSC-derived HSCs, we suggest that new preclinical models should be explored to fully evaluate cells generated from hiPSC sources.
authors: McMaster Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors: Ruth M
authors: RM
authors: Risueño
authors: Eleftherios
authors: E
authors: Sachlos
authors: Jong-Hee
authors: JH
authors: Lee
authors: Jung Bok
authors: JB
authors: Lee
authors: Seok-Ho
authors: SH
authors: Hong
authors: Eva
authors: E
authors: Szabo
authors: Mickie
authors: M
authors: Bhatia
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001853:Bone Marrow / Q000502:physiology; D001854:Bone Marrow Cells; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000502:physiology; D020869:Gene Expression Profiling; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000502:physiology* / Q000637:transplantation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D012038:Regeneration; D014183:Transplantation, Heterologous
chemical_list: D000943:Antigens, Differentiation; D035683:MicroRNAs