miR-146b-5p regulates bone marrow mesenchymal stem cell differentiation by SIAH2/PPARγ in aplastic anemia children and benzene-induced aplastic anemia mouse model

This study aimed to reveal the mechanism of miR-146b-5p in the differentiation of bone marrow mesenchymal stem cells (BMSCs) derived from children with aplastic anemia (AA). Here, we found that miR-146b-5p was highly expressed in BMSCs from children with AA, and the BMSCs surface markers expressions in BMSCs derived from children with AA and the healthy controls exerted no significant differences. Besides, the overexpression of miR-146b-5p in normal human-derived BMSCs promoted the adipogenic differentiation of BMSCs. Furthermore, miR-146b-5p negatively regulated SIAH2 luciferase activity, and the interference with miR-146b-5p reduced the stability of PPARγ protein and inhibited SIAH2-mediated ubiquitination of PPARγ protein. Besides, the interference with miR-146b-5p was beneficial for ameliorating AA in a mouse model of AA. Overall, our results found that miR-146b-5p was highly expressed in BMSCs from children with AA, and our further studies indicated that miR-146b-5p improved AA via promoting SIAH2-mediated ubiquitination of PPARγ protein.

本研究旨在揭示miR-146b-5p在再生障碍性贫血（aplastic anemia, AA）患儿骨髓间充质干细胞（bone marrow mesenchymal stem cells, BMSCs）分化过程中的作用机制。本研究发现，再生障碍性贫血患儿来源的骨髓间充质干细胞中miR-146b-5p呈高表达状态，且该类细胞与健康对照者来源的骨髓间充质干细胞的表面标志物表达水平无显著差异。此外，在正常人源骨髓间充质干细胞中过表达miR-146b-5p，可促进其成脂分化。进一步机制研究显示，miR-146b-5p负向调控SIAH2的荧光素酶活性；干扰miR-146b-5p的表达则可降低过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor γ, PPARγ）蛋白的稳定性，并抑制SIAH2介导的PPARγ蛋白泛素化。另外，在再生障碍性贫血小鼠模型中，干扰miR-146b-5p的表达有助于改善再生障碍性贫血病症。综上，本研究证实再生障碍性贫血患儿骨髓间充质干细胞中miR-146b-5p呈高表达，且进一步揭示miR-146b-5p通过促进SIAH2介导的PPARγ蛋白泛素化，从而发挥改善再生障碍性贫血的作用。