title: Arsenic trioxide and microRNA-204 display contrary effects on regulating adipogenic and osteogenic differentiation of mesenchymal stem cells in aplastic anemia.
abstract: Our previous studies have demonstrated that arsenic trioxide (ATO) had the clinical efficacy in treating patients with aplastic anemia (AA). However, the mechanisms remain to be elucidated. The important components of the bone marrow hematopoietic microenvironment, bone marrow mesenchymal stem cells (BMSCs), are often altered in AA patients. In this study, it was found that AA BMSCs were prone to be induced into adipocytes rather than osteoblasts. ATO treatment can at least partially restore the differentiation imbalance of AA BMSCs. We further identified miR-204 as a key regulator in AA BMSC differentiation. Luciferase reporter assay showed that miR-204 could directly bind to the 3'-untranslated region of Runx2 mRNA, a key transcription factor regulating osteogenesis. Moreover, adipogenic differentiation was promoted and osteogenic differentiation was inhibited in miR-204 over-expressed cells, whereas osteogenesis was enhanced and adipocyte formation was inhibited in cells that lost miR-204 function, which suggested its endogenous function. Together we showed that ATO could inhibit adipogenic differentiation, but promote osteogenic differentiation in AA BMSCs, providing a possible explanation for ATO clinical efficacy in AA patients. MiR-204 plays a key role in regulating BMSCs differentiation, and down-regulating miR-204 expression might be a novel strategy to treat AA.
authors.affiliation: Henan Key Lab of Experimental Haematology, Henan Institute of Haematology, Henan Tumor Hospital affiliated to Zhengzhou University, Zhengzhou 450008, China.
authors.forename: Junmei
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Henan Key Lab of Experimental Haematology, Henan Institute of Haematology, Henan Tumor Hospital affiliated to Zhengzhou University, Zhengzhou 450008, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Henan Key Lab of Experimental Haematology, Henan Institute of Haematology, Henan Tumor Hospital affiliated to Zhengzhou University, Zhengzhou 450008, China.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Song
authors.affiliation: Henan Key Lab of Experimental Haematology, Henan Institute of Haematology, Henan Tumor Hospital affiliated to Zhengzhou University, Zhengzhou 450008, China sunfbj@126.com.
authors.forename: Baijun
authors.initials: B
authors.lastname: Fang
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000741:Anemia, Aplastic / Q000473:pathology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis; D017931:DNA Primers; D006801:Humans; D016130:Immunophenotyping; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D035683:MicroRNAs / Q000235:genetics*; D010087:Oxides / Q000494:pharmacology*
chemical_list: D001152:Arsenicals; D050659:Core Binding Factor Alpha 1 Subunit; D017931:DNA Primers; C549404:MIRN204 microRNA, human; D035683:MicroRNAs; D010087:Oxides; C493709:RUNX2 protein, human; D000077237:Arsenic Trioxide
keywords: adipogenic differentiation; aplastic anemia; arsenic trioxide; mesenchymal stem cells; miR-204; osteogenic differentiation