title: Upregulation of miR-22 promotes osteogenic differentiation and inhibits adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells by repressing HDAC6 protein expression.
abstract: Mesenchmal stem cells (MSCs) can be differentiated into either adipocytes or osteoblasts, and a reciprocal relationship exists between adipogenesis and osteogenesis. Multiple transcription factors and signaling pathways have been reported to regulate adipogenic or osteogenic differentiation, respectively, yet the molecular mechanism underlying the cell fate alteration between adipogenesis and osteogenesis still remains to be illustrated. MicroRNAs are important regulators in diverse biological processes by repressing protein expression of their targets. Here, miR-22 was found to regulate adipogenic and osteogenic differentiation of human adipose tissue-derived mesenchymal stem cells (hADMSCs) in opposite directions. Our data showed that miR-22 decreased during the process of adipogenic differentiation but increased during osteogenic differentiation. On one hand, overexpression of miR-22 in hADMSCs could inhibit lipid droplets accumulation and repress the expression of adipogenic transcription factors and adipogenic-specific genes. On the other hand, enhanced alkaline phosphatase activity and matrix mineralization, as well as increased expression of osteo-specific genes, indicated a positive role of miR-22 in regulating osteogenic differentiation. Target databases prediction and validation by Dual Luciferase Reporter Assay, western blot, and real-time polymerase chain reaction identified histone deacetylase 6 (HDAC6) as a direct downstream target of miR-22 in hADMSCs. Inhibition of endogenous HDAC6 by small-interfering RNAs suppressed adipogenesis and stimulated osteogenesis, consistent with the effect of miR-22 overexpression in hADMSCs. Together, our results suggested that miR-22 acted as a critical regulator of balance between adipogenic and osteogenic differentiation of hADMSCs by repressing its target HDAC6.
authors.affiliation: Center of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Institute of Basic Medical Sciences and School of Basic Medicine, Beijing, People's Republic of China.
authors.forename: Shan
authors.initials: S
authors.lastname: Huang
authors.forename: Shihua
authors.initials: S
authors.lastname: Wang
authors.forename: Chunjing
authors.initials: C
authors.lastname: Bian
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.forename: Yang
authors.initials: Y
authors.lastname: Zeng
authors.forename: Hongling
authors.initials: H
authors.lastname: Li
authors.forename: Qin
authors.initials: Q
authors.lastname: Han
authors.forename: Robert Chunhua
authors.initials: RC
authors.lastname: Zhao
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D050156:Adipogenesis; D000273:Adipose Tissue / Q000166:cytology*; D000328:Adult; D015153:Blotting, Western; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation; D055815:Young Adult
chemical_list: C548375:MIRN22 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases