诱导多能干细胞的单细胞起源和特异性基因组变异来源组成的研究

体细胞重编程是生命科学研究领域的热点之一。诱导多能干细胞（iPS细胞）的获得无疑是体细胞重编程研究中的里程碑事件。IPS细胞在再生医学和疾病模型构建方面应用前景广泛，但其临床安全性以及在疾病模型构建上的适用性一直是争论的焦点，争论的核心在于由iPS细胞产生的功能性细胞是否是真实组织细胞的有效模拟。为了回答这一核心问题，需要利用多种研究手段、从多个研究角度了解体细胞->iPS细胞->功能细胞的细胞命运转换过程。本项目尝试利用基因组学分析技术和研究方法解析iPS细胞的单细胞起源和基因组变异的来源组成，对以下问题做出回答：重编程过程引入多少新的基因组变异，是否由重编程过程的选择所致？重编程过程是否在体细胞起源上存在细胞谱系的选择作用？期望从细胞基因组改变和细胞群体谱系变迁的角度，深入认识体细胞->iPS细胞的重编程过程，为iPS细胞的应用研究和安全性评价提供一些有意义的研究结果和思路。

Somatic cell reprogramming has been one of the hot areas of life science. Especially, the successful induction of somatic cells into induced pluripotent stem (iPS) cells is undoubtedly a landmark event, which has revolutionized our understanding of cell plasticity. IPS cells hold great promise in the field of regenerative medicine and are readily being used in personalized disease modeling, pathological studies and drug screening. However, this technology has not yet advanced to a stage where the therapeutic transplants and the iPS-based disease modeling have been deemed safe and applicable. The gut issue that people are worrying about is to what extent the iPS-derived tissue cells are the same as the real cells. A variety of research is certainly required to understand what has happened during the process of cell fate determination of somatic cells -> iPS cells -> adult cells. Here, we attempt to use the method of genomic analysis to resolve the single-cell origin of iPS cells as well as the source and the composition of the genomic mutations. Subsequently, the following two questions are expected to be answered. The first question is how many somatic mutations are actually introduced and then positively selected during reprogramming. And the second one is whether the reprogrammed somatic cells are lineage-selective in origin. We aim to trace the genomics instability and the alterations of cellular lineages during somatic cells->iPS cells in order to gain insight into the basis of reprogramming. The new knowledge and the new points of view collected from our future research would be of great benefit to the evaluation of iPS cells’ applications.