title: miR-146a-5p circuitry uncouples cell proliferation and migration, but not differentiation, in human mesenchymal stem cells.
abstract: Administration of mesenchymal stem cells (MSCs) has the potential to ameliorate degenerative disorders and to repair damaged tissues. The homing of transplanted MSCs to injured sites is a critical property of engraftment. Our aim was to identify microRNAs involved in controlling MSC proliferation and migration. MSCs can be isolated from bone marrow and umbilical cord Wharton's jelly (BM-MSCs and WJ-MSCs, respectively), and WJ-MSCs show poorer motility yet have a better amplification rate compared with BM-MSCs. Small RNA sequencing revealed that miR-146a-5p is significantly overexpressed and has high abundance in WJ-MSCs. Knockdown of miR-146a-5p in WJ-MSCs inhibited their proliferation yet enhanced their migration, whereas overexpression of miR-146a-5p in BM-MSCs did not influence their osteogenic and adipogenic potentials. Chemokine (C-X-C motif) ligand 12 (CXCL12), together with SIKE1, which is an I-kappa-B kinase epsilon (IKKε) suppressor, is a direct target of miR-146a-5p in MSCs. Knockdown of miR-146a-5p resulted in the down-regulation of nuclear factor kappa-B (NF-κB) activity, which is highly activated in WJ-MSCs and is known to activate miR-146a-5p promoter. miR-146a-5p is also downstream of CXCL12, and a negative feedback loop is therefore formed in MSCs. These findings suggest that miR-146a-5p is critical to the uncoupling of motility and proliferation of MSCs. Our miRNome data also provide a roadmap for further understanding MSC biology.
authors: Department of Life Sciences, Institute of Microbiology and Immunology, National Yang-Ming University, Linong St. Taipei, Taiwan 11221, Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Chenggong Rd. Taipei, Taiwan 11490, Department of Medical Research and Education, Taipei Veteran General Hospital, Shipai Rd., Taipei, Taiwan 11217, Stem Cell Research Center, National Yang-Ming University, Linong St. Taipei, Taiwan 11221, Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, Veteran General Hospital-Yang Ming Genome Research Center, National Yang-Ming University, Linong St. Taipei, Taiwan 11221, Department of Education and Research, Taipei City Hospital, Zhengzhou Rd. Taipei, Taiwan 10341 and Cancer Research Center and Genome Research Center, National Yang-Ming University, Linong St. Taipei, Taiwan 11221.
authors: Jui-Yu
authors: JY
authors: Hsieh
authors: Tse-Shun
authors: TS
authors: Huang
authors: Shu-Meng
authors: SM
authors: Cheng
authors: Wei-Shiang
authors: WS
authors: Lin
authors: Tsung-Neng
authors: TN
authors: Tsai
authors: Oscar K
authors: OK
authors: Lee
authors: Hsei-Wei
authors: HW
authors: Wang
mesh_terms: D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism / Q000502:physiology*
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D047908:Intracellular Signaling Peptides and Proteins; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; C583271:SIKE1 protein, human
references: Stem Cells Dev. 2012 Apr 10;21(6):911-22
references: 21732813
references: Br J Haematol. 2010 Feb;148(3):428-40
references: 19863541
references: Mol Cell Biol. 2011 Sep;31(17):3584-92
references: 21730286
references: Leukemia. 2012 Nov;26(11):2343-52
references: 22614176
references: J Biol Chem. 2006 Sep 15;281(37):26976-84
references: 16840782
references: Blood. 2004 Dec 1;104(12):3581-7
references: 15297308
references: Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):6139-44
references: 21444814
references: Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12481-6
references: 16885212
references: J Exp Med. 2002 Nov 4;196(9):1141-9
references: 12417625
references: Blood. 2004 Nov 1;104(9):2643-5
references: 15251986
references: Genome Biol. 2011 Jul 18;12(7):R64
references: 21767385
references: Stem Cells. 2008 Jan;26(1):146-50
references: 17932423
references: EMBO J. 2005 Dec 7;24(23):4018-28
references: 16281057
references: Breast Cancer Res Treat. 2010 Nov;124(2):377-86
references: 20182795
references: Stem Cells. 2006 May;24(5):1254-64
references: 16410389
references: Nucleic Acids Res. 2013 Jan;41(Database issue):D285-94
references: 23203880
references: J Cell Physiol. 2012 Jan;227(1):183-93
references: 21381024
references: J Immunol. 2010 May 1;184(9):4955-65
references: 20375304
references: Blood. 2010 Jan 14;115(2):265-73
references: 19965651
references: Genome Biol. 2009;10(3):R25
references: 19261174
references: Nucleic Acids Res. 2012 Jul;40(13):6001-15
references: 22492625
references: Stem Cells. 2011 May;29(5):847-57
references: 21394831
references: Cytotherapy. 2009;11(5):503-15
references: 19728189
references: Stem Cells Dev. 2010 Dec;19(12):1895-910
references: 20367285
references: Science. 1997 Apr 4;276(5309):71-4
references: 9082988
references: Biochem Biophys Res Commun. 2007 May 11;356(3):780-4
references: 17382293
references: BMC Med Genomics. 2011 Sep 19;4:65
references: 21923954
references: Mol Cancer. 2011 May 30;10:67
references: 21624123
references: Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2889-94
references: 18287052
references: Stem Cells Dev. 2012 Jul 20;21(11):2049-57
references: 22142236
references: Stem Cells. 2007 Jun;25(6):1384-92
references: 17332507
references: Stem Cells. 2010 Feb;28(2):357-64
references: 20039258
references: Oncogene. 2008 Sep 18;27(42):5643-7
references: 18504431
references: Cell Death Differ. 2011 Jun;18(6):985-95
references: 21164520
references: Cell Stem Cell. 2010 Jul 2;7(1):36-41
references: 20621048
references: Stem Cells. 2008 May;26(5):1186-201
references: 18308945
references: Prog Neurobiol. 2011 Oct;95(2):213-28
references: 21903148
references: Nucleic Acids Res. 2005 Nov 27;33(20):e179
references: 16314309
references: Blood. 2007 Feb 15;109(4):1422-32
references: 17038530
references: Stem Cells Dev. 2012 Sep 1;21(13):2531-40
references: 22375943
references: Bioinformatics. 2010 Jan 1;26(1):139-40
references: 19910308
references: Trends Biochem Sci. 2008 Apr;33(4):171-80
references: 18353649
references: Stem Cells. 2012 Aug;30(8):1746-55
references: 22696253
references: Stem Cells Dev. 2012 Sep 1;21(13):2508-19
references: 22384930
references: J Clin Invest. 2000 Dec;106(11):1331-9
references: 11104786
references: Stem Cells Dev. 2012 Jan 20;21(2):228-38
references: 21480782
references: RNA Biol. 2007 Nov;4(3):131-7
references: 18347435
references: Stem Cells. 2004;22(7):1330-7
references: 15579650
references: J Clin Invest. 2003 Jul;112(2):160-9
references: 12865405
references: Stem Cells. 2008 Oct;26(10):2496-505
references: 18583537
references: Cell Stem Cell. 2009 Mar 6;4(3):206-16
references: 19265660
references: Nat Med. 1999 Mar;5(3):309-13
references: 10086387
references: Blood. 2011 Aug 25;118(8):2275-84
references: 21730352
references: Cancer Res. 2010 Feb 15;70(4):1486-95
references: 20124483
references: Stem Cells. 2009 Apr;27(4):857-65
references: 19350687
references: Clin Cancer Res. 2011 Jul 1;17(13):4277-84
references: 21632853
references: Proteomics. 2009 Jan;9(1):20-30
references: 19116983
references: Blood. 2007 May 1;109(9):4055-63
references: 17197427
references: J Cell Sci. 2006 Jun 1;119(Pt 11):2204-13
references: 16684817
references: Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18366-71
references: 19017790
references: Nat Cell Biol. 2009 Mar;11(3):228-34
references: 19255566
references: PLoS One. 2009 Sep 28;4(9):e7192
references: 19784364
references: EMBO Rep. 2011 Jan;12(1):56-62
references: 21109779
references: Nat Cell Biol. 2012 Nov;14(11):1114-21
references: 23131918