Enhancing in vitro specification of definitive hematopoiesis from hemogenic endothelium through genetic and epigenetic modifications
通过遗传和表观遗传修饰增强造血内皮细胞确定性造血的体外规范
基本信息
- 批准号:321142297
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Fellowships
- 财政年份:2016
- 资助国家:德国
- 起止时间:2015-12-31 至 2018-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
The discovery and transplantation of hematopoietic stem cells (HSCs) is a success story of regenerative medicine. To meet the demand for HSCs, numerous attempts have been made to either expand the cells ex vivo or to generate them de novo from pluripotent stem cells. However, to date, these approaches remained largely unsuccessful.Using a genetic screening, the Daley lab has identified seven transcription factors, which in combination with growth factors are able to differentiate human pluripotent stem cells through an endothelial intermediate (hemogenic endothelium) in HSCs. The aim of this research project is to increase the efficiency of the differentiation protocol in order to generate sufficient cell numbers for subsequent down-stream applications such as drug screenings. For this, a reporter cell line will be used, which expresses a fluorescent protein under the control of the HSC-specific Runx1 promoter, thus allowing the identification of successfully specified HSCs. The goal is to identify essential transcription factors and to reduce the number of required factors for the specification into HSCs. Next, the efficiency of hematopoietic stem cell specification is to be increased by optimizing the transgene expression using a polycistronic lentiviral vector. Further, an siRNA screening should be performed to identified epigenetic modulators which inhibit the process of specification. Finally, the mechanisms by which the transcription factors and epigenetic modulators determine hematopoietic cell fate shall be deciphered by global gene expression analysis and transcription factor binding studies. In the long run, insights into the molecular mechanisms of HSC specification will allow generation of mature HSCs from pluripotent stem cells, which can serve as a potential source for clinical applications.
造血干细胞(HSCs)的发现和移植是再生医学的成功故事。为了满足对HSC的需求,已经进行了许多尝试来离体扩增细胞或从多能干细胞从头产生细胞。然而,迄今为止,这些方法仍然在很大程度上是不成功的。使用遗传筛选,戴利实验室已经确定了七个转录因子,它们与生长因子相结合,能够通过HSC中的内皮中间体(生血内皮)分化人类多能干细胞。该研究项目的目的是提高分化方案的效率,以便为后续的下游应用(如药物筛选)产生足够的细胞数量。为此,将使用报告细胞系,其在HSC特异性Runx1启动子的控制下表达荧光蛋白,从而允许鉴定成功指定的HSC。目标是鉴定必需的转录因子,并减少向HSC的特化所需的因子的数量。接下来,通过使用多顺反子慢病毒载体优化转基因表达来提高造血干细胞特化的效率。此外,应进行siRNA筛选以鉴定抑制特化过程的表观遗传调节剂。最后,转录因子和表观遗传调节剂决定造血细胞命运的机制将通过全局基因表达分析和转录因子结合研究来破译。从长远来看,对HSC特化的分子机制的深入了解将允许从多能干细胞产生成熟的HSC,这可以作为临床应用的潜在来源。
项目成果
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Dr. Caroline Maria Schuster-Kubaczka其他文献
Dr. Caroline Maria Schuster-Kubaczka的其他文献
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