title: Reprogramming of mouse somatic cells into pluripotent stem-like cells using a combination of small molecules.
abstract: Somatic cells can be reprogrammed to generate induced pluripotent stem cells (iPSCs) by overexpression of four transcription factors, Oct4, Klf4, Sox2, and c-Myc. However, exogenous expression of pluripotency factors raised concerns for clinical applications. Here, we show that iPS-like cells (iPSLCs) were generated from mouse somatic cells in two steps with small molecule compounds. In the first step, stable intermediate cells were generated from mouse astrocytes by Bmi1. These cells called induced epiblast stem cell (EpiSC)-like cells (iEpiSCLCs) are similar to EpiSCs in terms of expression of specific markers, epigenetic state, and ability to differentiate into three germ layers. In the second step, treatment with MEK/ERK and GSK3 pathway inhibitors in the presence of leukemia inhibitory factor resulted in conversion of iEpiSCLCs into iPSLCs that were similar to mESCs, suggesting that Bmi1 is sufficient to reprogram astrocytes to partially reprogrammed pluripotency. Next, Bmi1 function was replaced with Shh activators (oxysterol and purmorphamine), which demonstrating that combinations of small molecules can compensate for reprogramming factors and are sufficient to directly reprogram mouse somatic cells into iPSLCs. The chemically induced pluripotent stem cell-like cells (ciPSLCs) showed similar gene expression profiles, epigenetic status, and differentiation potentials to mESCs.
authors.affiliation: Laboratory of Cell Function Regulation, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Phil Jun
authors.initials: PJ
authors.lastname: Kang
authors.affiliation: Laboratory of Cell Function Regulation, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Jai-Hee
authors.initials: JH
authors.lastname: Moon
authors.affiliation: Laboratory of Cell Function Regulation, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea; StemLab, Venture Incubation Center Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Byung Sun
authors.initials: BS
authors.lastname: Yoon
authors.affiliation: Laboratory of Cell Function Regulation, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Solji
authors.initials: S
authors.lastname: Hyeon
authors.affiliation: Laboratory of Cell Function Regulation, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea; StemLab, Venture Incubation Center Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Jun
authors.affiliation: Laboratory of Cell Function Regulation, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Gyuman
authors.initials: G
authors.lastname: Park
authors.affiliation: Laboratory of Cell Function Regulation, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Wonjin
authors.initials: W
authors.lastname: Yun
authors.affiliation: Laboratory of Cell Function Regulation, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Jiyong
authors.initials: J
authors.lastname: Park
authors.affiliation: Laboratory of Cell Function Regulation, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Minji
authors.initials: M
authors.lastname: Park
authors.affiliation: Department of Pathology, College of Medicine, Korea University Guro Hospital, Seoul 152-703, Republic of Korea.
authors.forename: Aeree
authors.initials: A
authors.lastname: Kim
authors.affiliation: Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Kwang Youn
authors.initials: KY
authors.lastname: Whang
authors.affiliation: National Research Laboratory of Vascular Biology and Stem Cells, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.affiliation: Division of Animal Science, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Sejong
authors.initials: S
authors.lastname: Oh
authors.affiliation: Laboratory of Cell Function Regulation, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea. Electronic address: bioseung@korea.ac.kr.
authors.forename: Seungkwon
authors.initials: S
authors.lastname: You
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D053823:Hedgehog Proteins / Q000819:agonists*; D006888:Hydroxycholesterols / Q000494:pharmacology*; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011687:Purines / Q000494:pharmacology*; D014161:Transduction, Genetic
chemical_list: C489421:Bmi1 protein, mouse; D053823:Hedgehog Proteins; D006888:Hydroxycholesterols; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011687:Purines; C465570:Shh protein, mouse; C007997:25-hydroxycholesterol; D063150:Polycomb Repressive Complex 1; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; C470893:purmorphamine
keywords: Bmi1; Induced pluripotent stem cell (iPSC); Reprogramming; Small molecule compounds