title: Human fibroblast reprogramming to pluripotent stem cells regulated by the miR19a/b-PTEN axis.
abstract: Induction of pluripotent stem cells (iPSC) by defined transcription factors is the recognized canonical means for somatic reprogramming, however, it remains incompletely understood how individual transcription factors affect cell fate decisions during the reprogramming process. Here, we report induction of fibroblast reprogramming by various transcriptional factors is mediated by a miR19a/b-PTEN axis. cMyc, one of the four Yamanaka factors known to stimulate both somatic cell reprogramming and tumorigenesis, induced the expression of multiple mircoRNAs, miR-17 ∼ 92 cluster in particular, in the early stage of reprogramming of human fibroblasts. Importantly, miR-17 ∼ 92 cluster could greatly enhance human fibroblast reprogramming induced by either the four Yamanaka factors (Oct4, Sox2, Klf4, and cMyc, or 4F) or the first three transcriptional factors (Oct4, Sox2, and Klf4, or 3F). Among members of this microRNA cluster, miR-19a/b exhibited the most potent effect on stimulating fibroblst reprogramming to iPSCs. Additional studies revealed that miR-19a/b enhanced iPSC induction efficiency by targeted inhibition of phosphatase and tensin homolog (PTEN), a renowned tumor suppressor whose loss-of-function mutations were found in multiple human malignancies. Our results thus demonstrate an important role of miR-19a/b-PTEN axis in the reprogramming of human fibroblasts, illustrating that the somatic reprogramming process and its underlying regulation pathways are intertwined with oncogenic signaling in human malignancies.
authors.affiliation: Innovation Center for Cell Biology, School of Life Science, University of Science and Technology of China, Hefei, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: He
authors.affiliation: Innovation Center for Cell Biology, School of Life Science, University of Science and Technology of China, Hefei, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Innovation Center for Cell Biology, School of Life Science, University of Science and Technology of China, Hefei, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.affiliation: Innovation Center for Cell Biology, School of Life Science, University of Science and Technology of China, Hefei, China.
authors.forename: Yingli
authors.initials: Y
authors.lastname: Han
authors.affiliation: Innovation Center for Cell Biology, School of Life Science, University of Science and Technology of China, Hefei, China.
authors.forename: Xiuying
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Center for Reproductive Medicine, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, China.
authors.forename: Guixiang
authors.initials: G
authors.lastname: Zhou
authors.affiliation: Department of Pathology, School of Medicine, Anhui University, Hefei, China.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Innovation Center for Cell Biology, School of Life Science, University of Science and Technology of China, Hefei, China.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Innovation Center for Cell Biology, School of Life Science, University of Science and Technology of China, Hefei, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
mesh_terms: D002454:Cell Differentiation; D002460:Cell Line; D065150:Cellular Reprogramming; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D062085:RNA, Long Noncoding; D012190:Retroviridae / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C568997:MIR17HG, human; C549214:MIRN19A microRNA, human; D035683:MicroRNAs; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D062085:RNA, Long Noncoding; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
references.citation: Cell Stem Cell. 2008 Jan 10;2(1):10-2
references.pmid: 18371415
references.citation: Nature. 2013 Oct 3;502(7469):65-70
references.pmid: 24048479
references.citation: Nat Rev Cancer. 2008 Jan;8(1):51-6
references.pmid: 18046334
references.citation: Nat Cell Biol. 2011 Oct 23;13(11):1353-60
references.pmid: 22020437
references.citation: Nature. 2011 Jun 08;474(7350):225-9
references.pmid: 21654807
references.citation: Cell Stem Cell. 2011 Jun 3;8(6):633-8
references.pmid: 21620789
references.citation: Stem Cells. 2010 Apr;28(4):713-20
references.pmid: 20201064
references.citation: Nature. 2005 Jun 9;435(7043):839-43
references.pmid: 15944709
references.citation: Cell. 2013 May 23;153(5):963-75
references.pmid: 23706735
references.citation: Nat Methods. 2009 Nov;6(11):805-8
references.pmid: 19838168
references.citation: Cell Stem Cell. 2010 Nov 5;7(5):618-30
references.pmid: 20888316
references.citation: Cell Stem Cell. 2013 Sep 5;13(3):261-2
references.pmid: 24012365
references.citation: Genes Dev. 2009 Dec 15;23(24):2806-11
references.pmid: 20008931
references.citation: Cell Stem Cell. 2011 Apr 8;8(4):376-88
references.pmid: 21474102
references.citation: Cell. 2012 Sep 14;150(6):1209-22
references.pmid: 22980981
references.citation: Nature. 2007 Jul 19;448(7151):313-7
references.pmid: 17554338
references.citation: Cell Stem Cell. 2012 Aug 3;11(2):179-94
references.pmid: 22862944
references.citation: Cell. 2009 Jan 23;136(2):364-77
references.pmid: 19167336
references.citation: Cell. 2013 Mar 14;152(6):1324-43
references.pmid: 23498940
references.citation: Cell. 2006 Aug 25;126(4):663-76
references.pmid: 16904174
references.citation: Nat Biotechnol. 2009 May;27(5):459-61
references.pmid: 19363475
references.citation: Cell Res. 2013 Jan;23(1):142-56
references.pmid: 23266889
references.citation: Nature. 2012 Aug 30;488(7413):652-5
references.pmid: 22902501
references.citation: Cancer Cell. 2012 Oct 16;22(4):524-35
references.pmid: 23079661
references.citation: Stem Cells. 2012 Aug;30(8):1645-54
references.pmid: 22696098
references.citation: EMBO J. 2011 Mar 2;30(5):823-34
references.pmid: 21285944
references.citation: Nature. 2010 Feb 4;463(7281):621-6
references.pmid: 20054295
references.citation: Cell Res. 2011 Nov;21(11):1634-7
references.pmid: 21876560
references.citation: Cell. 2012 Mar 30;149(1):22-35
references.pmid: 22464321
references.citation: Genes Dev. 2009 Dec 15;23(24):2839-49
references.pmid: 20008935
references.citation: J Mammary Gland Biol Neoplasia. 2004 Jan;9(1):27-37
references.pmid: 15082916
references.citation: Stem Cells. 2008 Aug;26(8):1998-2005
references.pmid: 18511599
references.citation: Stem Cells. 2014 Feb;32(2):349-63
references.pmid: 23765875
references.citation: Cell. 2010 Oct 15;143(2):313-24
references.pmid: 20946988
references.citation: Cell. 2007 Nov 30;131(5):861-72
references.pmid: 18035408
references.citation: Cell Stem Cell. 2013 Sep 5;13(3):341-50
references.pmid: 23871606
references.citation: Nature. 2008 Jul 3;454(7200):49-55
references.pmid: 18509334
references.citation: Nature. 2009 Apr 9;458(7239):762-5
references.pmid: 19219026
references.citation: Science. 2007 Dec 21;318(5858):1917-20
references.pmid: 18029452
references.citation: Genes Cancer. 2010 Jun;1(6):660-7
references.pmid: 21779463