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From Fibroblasts to iPS Cells: Induced Pluripotency by Defined Factors
Patient-specific pluripotent cells may serve as a limitless source of transplantable tissue to treat a number of human blood and degenerative diseases without causing immune rejection. Recently, isolation of patient-specific induced pluripotent stem (iPS) cells was achieved by transducing fibroblasts with four transcription factors, Oct4, Sox2, Klf4, and c-Myc. However, the use of oncogenes and retrovirus in the current iPS cell establishment protocol raises safety concerns. To generate clinical quality iPS cells, the development of novel reprogramming methods that avoid permanent genetic modification is highly desired. The molecular mechanisms that mediate reprogramming are essentially unknown. We argue that establishment of a stable and self-sustainable ES-specific transcriptional regulatory network is essential for reprogramming. Such a system should include expression of Oct4, Sox2, Nanog and probably other pluripotenty-promoting factors from endogenous loci and establishment of a permissive epigenetic state to maintain such expression. In addition, though not yet proven experimentally, overcoming cellular senescence of fibroblasts by inactivating Rb and p53 pathways and up-regulating telomerase activity may also be required.
从成纤维细胞到 iPS 细胞: 通过特定的因子来诱导多能性
病人特异性多功能细胞提供了一个无限的来源用于组织移植治疗一些人类血液和退行性疾病而不引起免疫排斥。最近，通过给成纤维细胞转移四个因子 Oct4，Sox2，Klf4 和 c -Myc 能够获得病人特异性诱导干细胞 iPS 细胞。然而在现在的 iPS 技术中使用逆转录病毒和癌基因使得其在临床上有潜在的安全性问题。为了产生符合临床质量的 iPS 细胞技术，发展新的诱导方法，可以避免永久的基因改良技术必须优先考虑。重编程的分子机制在本质上是未知的。我们认为，建立一种稳定、自我维持的 ES 特异性转录调节网络对于重编程是非常重要的。这样一个系统应包括 Oct4，Sox2，Nanog 的表达，可能还有其它内源性的多能性促进因子，以及建立一种表观遗传学的改变来维持这种状态，此外，尽管还没经实验证明，用于克服成纤维细胞衰老的激活的 Rb 和 P53 的通路和端粒酶的活性上调，这些也是必须的。
