盐酸二甲双胍抑制骨髓间充质干细胞向脂肪细胞分化和促进造血因子表达的作用和分子机理

Excess adipogenesis in bone marrow is a typical pathological feature of many anemia syndromes, such as aplastic anemia and hypoproliferative myelodyspoastic syndromes. Excess adipogenesis was considered as a secondary alterations following impaired hematopoiesis in the past, while recently it has been showed that adipocytes have negative effects on normal hematopoiesis.The detailed molecular mechanisms is still largely unknown and there is also no highly effective target drugs against excess adipogenesis in bone marrow. According to our recent work in analyzing the similarity between transcriptome of adipogenesis of bone marrow mesenchymal stem cells (MSC) and pharmocogenomics, we predict that metformin hydrochloride may have bidirectional effects on MSC, i.e. negative effect on adipogenesis and positive effect on hematopoiesis. Our preliminary data have verified these predicative effects that metformin hydrochloride could inhibit adipogenesis of human MSC in vitro. In this application, we will further systemically study the effects of metformin on: (1) adipogenesis of human MSC in vitro and identify the key genes and proteins and their related molecular mechanism; (2) osteogenesis of human MSC in vitro and identify the key genes and proteins and their related molecular mechanism; (3) on hematopoiesis factor expression and idnetify the key genes and proteins. The ultimate purpose of the present application is to screen for the new non-patent drug targets for the treatment of anemia syndromes via inhibiting the adipogenesis of MSC.

骨髓过度脂肪化是多种贫血性疾病共有的病理组织学特征，如常见的再生障碍性贫血和某些骨髓增生异常综合征等。一般认为骨髓脂肪化是继发现象，近年证实脂肪细胞可抑制造血，但缺乏骨髓过度脂肪化分子机制的系统研究，也无针对性治疗药物。申请人将药物基因组学和骨髓间充质干细胞（MSC）向脂肪细胞分化的转录组进行相似性分析发现，二甲双胍对MSC可能兼有抑制向脂肪细胞及促进向成骨细胞分化的作用，并已初获验证。本课题拟在前期证实二甲双胍可抑制MSC成脂化的基础上，利用体外人MSC脂向分化体系，采用人类全基因组表达芯片等技术，研究二甲双胍：⑴抑制脂向分化作用，筛选关卡基因并在分子水平验证，探讨其分子机制；⑵促进MSC向成骨细胞分化的作用，筛选其中关卡基因并在分子水平进行验证，探讨相关分子机制；⑶促进骨髓间充质干细胞表达人类造血生长因子的作用。为筛选通过抑制骨髓过度脂肪化促进正常造血恢复的新型非专利药物提供指导。

骨髓过度脂肪化是多种贫血性疾病共有的病理组织学特征，如常见的再生障碍性贫血和某些骨髓增生异常综合征等。一般认为骨髓脂肪化是继发现象，近年证实脂肪细胞可抑制造血，但缺乏骨髓过度脂肪化分子机制的系统研究，也无针对性治疗药物。申请人将药物基因组学和骨髓间充质干细胞（MSC）向脂肪细胞分化的转录组进行相似性分析发现，包括盐酸二甲双胍的多种药物在内，对MSC可能兼有抑制向脂肪细胞及促进造血的作用。本课题：⑴采用疾病基因组学和药物基因组学相似性分析的方法，筛选出了吗丁啉、橘皮苷、达哌啶醇、羟苄羟麻黄碱、达那唑、茴香霉素、二甲双胍、双氟拉松等可能兼有抑制骨髓间充质干细胞过度脂向分化和促进造血的作用；⑵利用体外人MSC脂向诱导分化体系，证实二甲双胍可抑制人骨髓间充质干细胞的成脂化作用；⑶ 采用人类全基因组表达芯片等技术发现，盐酸二甲双胍的抑制脂向分化和促进造血作用，与AMPK基因无关，但可能与LKB1基因有关。本课题为老药新用提供了一条新的思路，为重型再生障碍性贫血的治疗药物提供了指导。