Arsenic trioxide and microRNA-204 display contrary effects on regulating adipogenic and osteogenic differentiation of mesenchymal stem cells in aplastic anemia  

作　　者：Junmei Zhao Chao Wang Yongping Song Baijun Fang 

机构地区：[1]Henan Key Lab of Experimental Haematology, Henan Institute of Haematology, Henan Tumor Hospital affiliated to Zhengzhou University,Zhengzhou 450008, China

出　　处：《Acta Biochimica et Biophysica Sinica》2014年第10期885-893,共9页生物化学与生物物理学报（英文版）

基　　金：This study was supported by the grants from the National Natural Science Foundation of China （81070398 and 81370661）.

摘　　要：Our previous studies have demonstrated that arsenic triox- ide （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 differenti- ation 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 dir- ectly bind to the 3＇-untranslated region ofRunx2 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, pro- viding 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.Our previous studies have demonstrated that arsenic triox- ide （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 differenti- ation 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 dir- ectly bind to the 3＇-untranslated region ofRunx2 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, pro- viding 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.

关 键 词：arsenic trioxide aplastic anemia mesenchymal stem cells osteogenic differentiation adipogenic differentiation miR-204 

分 类 号：Q813.1[生物学—生物工程] TS974.22[轻工技术与工程]