title: Establishment of leukemia inhibitory factor (LIF)-independent iPS cells with potentiated Oct4.
abstract: Leukemia inhibitory factor (LIF) is widely used to establish and maintain naïve pluripotent stem cells, including mouse embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Although the combination of chemical inhibitors called 2i can establish mouse iPSCs without LIF from primed pluripotent stem cells, it has been difficult, if not impossible, to establish mouse iPSCs from differentiated somatic cells without LIF. We previously showed that the fusion gene of the transactivation domain of MyoD and the full-length Oct4 (M3O) increases the efficiency of making iPSCs when transduced into fibroblasts along with Sox2, Klf4, and c-Myc (M3O-SKM). Here, we report that M3O-SKM allows for establishment of iPSCs without exogenous LIF from mouse embryonic fibroblasts. The established iPSCs remained undifferentiated and maintained pluripotency over 90 days without LIF as long as M3O was expressed. The iPSCs upregulated miR-205-5p, which was potentially involved in the LIF-independence by suppressing the two signaling pathways inhibited by 2i. The result indicates that potentiated Oct4 can substitute for the LIF signaling pathway, providing a novel model to link Oct4 and LIF, two of the most significant players in naïve pluripotency.
authors.affiliation: Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota 55455, USA; Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hirai
authors.affiliation: Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota 55455, USA; Division of Endocrinology, Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Meri
authors.initials: M
authors.lastname: Firpo
authors.affiliation: Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota 55455, USA; Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota 55455, USA. Electronic address: kikyo001@umn.edu.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Kikyo
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D053605:Leukemia Inhibitory Factor; D035683:MicroRNAs; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human
keywords: Induced pluripotent stem cells; Leukemia inhibitory factor; Pluripotency; miRNA