细胞命运转变——谱系重编程技术研究进展

体细胞核移植和诱导多能干细胞技术表明已分化的体细胞可以转变命运。最近的研究再一次验证了成熟体细胞可以通过外源转录因子的导入,直接重编程为其他类型的体细胞或祖细胞。这种重编程技术称为谱系重编程(Lineage reprogramming)。这项技术不仅在再生医学领域具有广阔的应用前景,而且在动物生物技术中也应用广泛。它不但避免了伦理争议,还提供了便利的重编程方法,同时也为基因表达调控的研究提供了重要的手段。文章从谱系重编程的方式、谱系重编程的特点及应用前景等3个方面进行了综述,旨在对相关领域的研究人员起到借鉴作用。     

核移植与诱导多能干细胞技术在体细胞重编程研究中的应用

体细胞重编程是指分化的体细胞在特定的条件下被逆转后恢复到多能性或全能性状态,或者形成多能干细胞系,或者形成早期胚胎然后发育成一个新的个体的过程。诱导体细胞重编程的方法有许多,如核移植（nuclear transfer,NT）、细胞融合、细胞培养和通过导入特定因子获得诱导多能干（induced pluripotent stem,iPS）细胞的方法等。其中核移植和iPS技术是到目前为止诱导体细胞为多能干细胞最为完全、最具有运用于临床再生医学潜能的方法。然而,它们的效率都很低,机制也不清楚,如何将两个方法结合在一起,提高重编程的效率,揭示重编程的机制,进而促进其在患者特异性治疗中的运用将是下阶段的努力方向。     

Cellular reprogramming of somatic cells

The process of 'cell reprogramming' can be achieved by somatic cell nuclear transfer, cell fusion with embryonic stem cells, exposure to stem cell extracts, or by inducing pluripotentcy mediated by defined factors giving rise to what are termed induced pluripotent stem cells. More recently, the fate of a somatic cell can be directly induced to uptake other cell fates, termed lineage-specific reprogramming, without the need to de-differentiate the cells to a pluripotent state. In this review we will describe the different methods of reprogramming somatic cells.     

体细胞核移植后表观遗传重编程的异常及其修复

体细胞核移植(Somatic cell nuclear transfer, SCNT)是指将高度分化的体细胞移入到去核的卵母细胞中发育并最终产生后代的技术。然而, 体细胞克隆的总体效率仍然处于一个较低的水平, 主要原因之一是由于体细胞供体核不完全的表观遗传重编程, 包括DNA甲基化、组蛋白乙酰化、基因组印记、X染色体失活和端粒长度等修饰出现的异常。使用一些小分子化合物以及Xist基因的敲除或敲低等方法能修复表观遗传修饰错误, 辅助供体核的重编程, 从而提高体细胞克隆效率, 使其更好地应用于基础研究和生产实践。文章对体细胞核移植后胚胎发育过程中出现的异常表观遗传修饰进行了综述, 并着重论述了近年来有关修复表观遗传错误的研究进展。     

Molecular insights into the heterogeneity of telomere reprogramming in induced pluripotent stem cells

Rejuvenation of telomeres with various lengths has been found in induced pluripotent stem cells (iPSCs). Mechanisms of telomere length regulation during induction and proliferation of iPSCs remain elusive. We show that telomere dynamics are variable in mouse iPSCs during reprogramming and passage, and suggest that these differences likely result from multiple potential factors, including the telomerase machinery, telomerase-independent mechanisms and clonal influences including reexpression of exogenous reprogramming factors. Using a genetic model of telomerase-deficient (Terc(-/-) and Terc(+/-)) cells for derivation and passages of iPSCs, we found that telomerase plays a critical role in reprogramming and self-renewal of iPSCs. Further, telomerase maintenance of telomeres is necessary for induction of true pluripotency while the alternative pathway of elongation and maintenance by recombination is also required, but not sufficient. Together, several aspects of telomere biology may account for the variable telomere dynamics in iPSCs. Notably, the mechanisms employed to maintain telomeres during iPSC reprogramming are very similar to those of embryonic stem cells. These findings may also relate to the cloning field where these mechanisms could be responsible for telomere heterogeneity after nuclear reprogramming by somatic cell nuclear transfer.