iPS细胞技术不仅为体细胞重编程机制的研究提供了新的模型,而且为疾病发生发展相关机制的研究和特异性细胞治疗开创了道路。但是以目前技术制备的iPS细胞由于潜在的致癌性和重编程效率低，大大限制了其在临床上的应用，因此迫切需要研发新的安全高效的iPS细胞制备技术。我们在实验中发现，当使用小分子化合物将细胞的异染色质变构为常染色质时，细胞发生去分化现象，表明体细胞的再编程可以通过细胞内异染色质的结构改变得以实现。根据这一发现，我们对60多个影响染色质结构的小分子化合物进行了组合筛选。目前我们已经筛选出一组四个小分子化合物，并用其将人成纤维细胞诱导为多能干细胞。本项目旨在对异染色质变构在体细胞再编程过程中的作用和分子机制进行深入研究，并对新研发的iPS细胞制备技术进一步的鉴定和完善。本项目提出的新的理论机制和方法，将会为iPS细胞技术的临床应用开辟新的途径。

iPS cell technology has not only provided a new model for somatic cell reprogramming, but also has opened up the way for the development of specific disease models and personalized cell therapies. However，due to the potential carcinogenicity and low reprogramming efficiency, clinical application of the iPS cells derived with the current generation methods is badly limited. There is an urgent need to develop novel iPS cell generation technique that is safe and efficient. We observed that transformation of heterochromatin to euchromatin led to dedifferentiation of somatic cells, implying that reprogramming of somatic cells can be achieved by heterochromatin remodeling. Based on this observation, we screened more than 60 small molecule compounds that have influence on chromatin structure, and have worked out a combination of 4 compounds, with which we have been able to induce human fibroblast cells to iPS cells. In this project we aim to investigate the role and the molecular mechanisms of heterochromatin remodeling in the process of somatic cell reprogramming in-depth, and to optimize the new iPS cell generation method that we have just developed. The new theory and methods proposed in this project will pave the way for clinical applications of iPS cell technology.

将人的体细胞诱导为多能干细胞为自体细胞生物治疗开创了一个新的阶段，以小分子化合物诱导体细胞重编程是当前干细胞研究领域研究的热点。在本项目中，我们成功的使用小分子化合物将人成纤维细胞在2-3周内诱导为多能干细胞。结果表明，诱导的多能干细胞表达ES细胞的特异性标志物SSEA4和ALP，可以形成胚状体，并可在体外被定向诱导分化为不同胚层的组织细胞。此外我们观察到，诱导药物对细胞的异染色体结构有明显的变构效应。上述发现表明，我们采用小分子化合物变构异染色体实现体细胞重编程的技术具有重要的应用价值，为该技术下一步的临床试验及应用奠定了坚实的基础。