MDS源性特异性人工诱导多能干细胞（iPSCs）细胞系构建/定向髓系分化诱导策略及相关分子机制研究

The myelodysplastic syndrome (MDS) are heterogenic myeloid clonal disease .which are originated from hematopoietic disease. The high risk MDS are .inclined to be transformed to acute myelocytic leukemia (AML). The .Pathogenesis of MDS may related to various genetic abnormalities and the change ofone marrow microenvironment, yet the exact mechanism of it has not been clarified. The common disease models for investigating the Pathogenesis and treatment of MDS are murine models which established by transgene strategy, gene manipulation or heterograft of human MDS etc. Most of them only can mimic .the MDS symptoms of ineffective hematopoiesis in bone marrow. The somatic cells reprogramming technology provided a new strategy of .establishing the disease models for studying the Pathogenesis of some genetic disorder diseases. The current study propose to establish iPSCs cell line from highrisk MDS﹙MDS-RAEB-II﹚ patients bone marrow cells, and direct differentiate it to myeloid lineage. Comparing the myeloid lineage differentiation ability of MDS-iPSCs and normal bome marrow derived iPSCs, screening the the key regulatory gene clusters and signalling transduction pathways which are related to MDS bone marrow reprogramming and its myeloid differentiation. Thus providing a new strategy for induction differentiation therapy of MDS.

骨髓增生异常综合征﹙MDS﹚是一组起源于造血干细胞的异质性髓系克隆性疾病。高危型MDS极易向急性髓系白血病﹙AML﹚转化，诊断及治疗困难。MDS发病机制可能与多种遗传学异常及骨髓微环境改变有关，但确切机制尚未阐明。目前研究MDS发病机制及治疗的疾病模型多为转基因法、基因改造法或异种移植人MDS细胞法等构建的小鼠模型，仅可从骨髓无效造血方面模拟MDS疾病特征。目前尚无有效的MDS体外模型用于研究其确切的分子病理机制以发现验证更为有效的治疗手段。体细胞重编程构建iPSCs技术的发展为体外构建疾病模型，研究疾病发生发展规律提供新的策略。本研究提出采用体细胞重编程技术，构建高危型MDS﹙MDS-RAEB-II﹚患者骨髓细胞来源iPSCs，体外诱导其向髓系定向分化，筛选鉴定MDS细胞重编程及向髓系定向分化的关键调控基因簇及相关信号转导通路。为高危型MDS 的诱导分化治疗提供新的思路。

骨髓增生异常综合征﹙MDS﹚是一组起源于造血干细胞的异质性髓系克隆性疾病。高危型MDS极易向急性髓系白血病﹙AML﹚转化，诊断及治疗困难。MDS发病机制可能与多种遗传学异常及骨髓微环境改变有关，但确切机制尚未阐明。目前研究MDS发病机制及治疗的疾病模型多为转基因法、基因改造法或异种移植人MDS细胞法等构建的小鼠模型，仅可从骨髓无效造血方面模拟MDS疾病特征。目前尚无有效的MDS体外模型用于研究其确切的分子病理机制以发现验证更为有效的治疗手段。体细胞重编程构建iPSCs技术的发展为体外构建疾病模型，研究疾病发生发展规律提供新的策略。本研究提出采用体细胞重编程技术，构建高危型MDS﹙MDS-RAEB-II﹚患者骨髓细胞来源iPSCs，体外诱导其向髓系定向分化，筛选鉴定MDS细胞重编程及向髓系定向分化的关键调控基因簇及相关信号转导通路。为高危型MDS 的诱导分化治疗提供新的思路。课题组成功收集临床明确诊断高危型MDS （MDS-RAEB-I或MDS-RAEB-II,）患者骨髓细胞5例。课题组在前期实验成功收集的临床明确诊断高危型MDS患者的骨髓细胞（BM）的基础上，对其单个核细胞进行了内皮祖细胞（EPC）的提取和扩增，作为正常对照iPSCs的来源细胞。目前已成功建立2个EPC细胞系，并进行重编程构建iPSCs细胞系。高危型MDS患者的骨髓细胞（BM）来源的iPSCs向红系和髓系分化受阻，同一患者EPC来源的iPSCs可向红系和髓系分化。基因表达谱芯片相关工作，目前正在进一步推进。

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