title: miR-34a inhibits differentiation of human adipose tissue-derived stem cells by regulating cell cycle and senescence induction.
abstract: MicroRNAs (miRNAs) are critical in the maintenance, differentiation, and lineage commitment of stem cells. Stem cells have the unique property to differentiate into tissue-specific cell types (lineage commitment) during cell division (self-renewal). In this study, we investigated whether miR-34a, a cell cycle-regulating microRNA, could control the stem cell properties of adipose tissue-derived stem cells (ADSCs). First, we found that the expression level of miR-34a was increased as the cell passage number was increased. This finding, however, was inversely correlated with our finding that the overexpression of miR-34a induced the decrease of cell proliferation. In addition, miR-34a overexpression decreased the expression of various cell cycle regulators such as CDKs (-2, -4, -6) and cyclins (-E, -D), but not p21 and p53. The cell cycle analysis showed accumulation of dividing cells at S phase by miR-34a, which was reversible by co-treatment with anti-miR-34a. The potential of adipogenesis and osteogenesis of ADSCs was also decreased by miR-34a overexpression, which was recovered by co-treatment with anti-miR-34a. The surface expression of stem cell markers including CD44 was also down-regulated by miR-34a overexpression as similar to that elicited by cell cycle inhibitors. miR-34a also caused a significant decrease in mRNA expression of stem cell transcription factors as well as STAT-3 expression and phosphorylation. Cytokine profiling revealed that miR-34a significantly modulated IL-6 and -8 production, which was strongly related to cellular senescence. These data suggest the importance of miR-34a for the fate of ADSCs toward senescence rather than differentiation.
authors.affiliation: Medical Research Institute & Adult Stem Cell Research Institute, Department of Obstetrics and Gynecology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 108 Pyung-Dong, Jongro-Gu, Seoul, Republic of Korea; Department of Clinical Laboratory Science, Wonkwang Health Science University, 514 Iksandaero, Iksan, Jeonbuk, Republic of Korea.
authors.forename: Ho
authors.initials: H
authors.lastname: Park
authors.affiliation: Wide River Institute of Immunology, Seoul National University College of Medicine,103 Daehak-ro, Jongno-gu, Seoul, Republic of Korea.
authors.forename: Hyeon
authors.initials: H
authors.lastname: Park
authors.affiliation: Medical Research Institute & Adult Stem Cell Research Institute, Department of Obstetrics and Gynecology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 108 Pyung-Dong, Jongro-Gu, Seoul, Republic of Korea.
authors.forename: Ha-Jin
authors.initials: HJ
authors.lastname: Pak
authors.affiliation: Nslim clinic, Seoul, Republic of Korea.
authors.forename: Dong-Yun
authors.initials: DY
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology and Pain Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Yun-Hong
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology and Pain Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Won-Jun
authors.initials: WJ
authors.lastname: Choi
authors.affiliation: Department of Orthopedic Surgery Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Wide River Institute of Immunology, Seoul National University College of Medicine,103 Daehak-ro, Jongno-gu, Seoul, Republic of Korea; BK21 Plus Biomedical Science Project, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, Republic of Korea.
authors.forename: Jung-Ah
authors.initials: JA
authors.lastname: Cho
authors.affiliation: Medical Research Institute & Adult Stem Cell Research Institute, Department of Obstetrics and Gynecology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 108 Pyung-Dong, Jongro-Gu, Seoul, Republic of Korea.
authors.forename: Kyo-Won
authors.initials: KW
authors.lastname: Lee
mesh_terms: D050156:Adipogenesis / Q000235:genetics*; D000273:Adipose Tissue / Q000166:cytology; D002453:Cell Cycle / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics*; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology; D010012:Osteogenesis / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology
chemical_list: C508606:CXCL8 protein, human; D018797:Cell Cycle Proteins; D018960:Hyaluronan Receptors; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D020320:Oligoribonucleotides, Antisense; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: Adipose-derived Mesenchymal Stem Cells; Cell Cycle; Senescence; miR-34a