Role of EMT Mediators in Differentiation of Hematopoietic Stem Cells and Interaction with the Microenvironment

HSC是自我更新和分化过程之间的严格控制的基础，以防止耗竭或恶性转化。更好地了解调节造血干细胞自我更新和分化的机制不仅对理解疾病有希望，而且还可以探索将替代干细胞来源用于再生医学的新可能性。在胚胎发育过程中，细胞命运的决定是通过上皮细胞向间充质细胞谱系的转化来执行的，称为EMT（上皮细胞向间充质细胞转化），这是一个涉及细胞结构变化、与周围环境相互作用和迁移的强制性过程。转录因子家族的一些成员，包括Snail、Zebs和Twists，在EMT过程中起着至关重要的作用。然而，很少有人知道这些转录因子在造血干细胞分化的调节中的生理作用。在这项研究中，中国和德国的合作者将使用人诱导多能干细胞和转基因小鼠作为体外和体内模型，研究EMT相关转录因子在不同造血谱系分化中的作用。人类iPSC将被遗传修饰，以利用新的TALEN方法获得一致的敲入/敲出多能干细胞系。转基因动物是基于已经产生并准备用于本研究的所需基因序列的条件性缺失。本研究的预期结果将提供造血系统中EMT相关转录因子调控机制的新知识，并可能导致干细胞在临床应用中的更好利用。

HSCs underlie a strict control between self renewal and differentiation processes to prevent exhaustion or malignant transformation. Better understanding of mechanisms that regulate hematopoietic stem cell self renewal and differentiation not only holds the promise on understanding diseases, but also may enable to explore new possibilities to use alternative sources of stem cells for regenerative medicine. During the embryonic development, the determination of cell fate is executed by transformation from epithelial to mesenchymal cell lineage, termed as EMT (epithelial to mesenchymal transition), a compelling process involving changes in cell structure, interaction with the surrounding environment and migration. Some members of transcription factor families including Snails, Zebs and Twists have been associated to play a crucial role in the EMT process. However, little is known about the physiological role of these transcription factors in regulation of hematopoietic stem cells differentiation. In this study, the collaborators between China and Germany will use human induced pluripotent stem cells and transgenic mice as in vitro and in vivo models to investigate the role of EMT-related transcription factors in differentiation of different hematopoietic lineages. Human iPSCs will be genetically modified to derive consistent knock-in/out pluripotent stem cell lines utilizing the novel TALEN approach. The transgenic animals are based on conditional deletion of the desired gene sequences which were already generated and ready to use for this study. The anticipated results of this study will provide new knowledge of the regulatory mechanism by EMT-associated transcription factors in the hematopoietic system and may lead to better utilization of stem cells in the clinical use.