Heffernan Corey, Sumer Huseyin, Verma Paul J
Reprogramming and Stem Cell Laboratory, Monash Institute of Medical Research, Monash University, Clayton, VIC, Australia.
J Stem Cells. 2011;6(3):109-27.
Proviral expression of early development genes Oct4 and Sox2, in concert with cMyc and Klf4 or Nanog and Lin28, can induce differentiated cells to adopt morphological and functional characteristics of pluripotency indistinguishable from embryonic stem cells. Termed induced pluripotent stem (iPS) cells, in mice the pluripotency of these cells was confirmed by altered gene/surface antigen expression, remodeling of the epigenome, ability to contribute to embryonic lineages following blastocyst injection and commitment to all three germ layers in teratomas and liveborn chimeras. Importantly, in vitro directed differentiation of iPS cells yield cells capable of treating mouse models of humanized disease. Despite these impressive results, iPS cell conversion is frustratingly inefficient. Also, the unpredictable and random mutagenesis imposed on the host cell genome, inherent with integrative viral methodologies, continues to hamper use of these cells in a therapeutic setting. This has initiated exploration of non-integrating strategies for generating iPS cells. Here, we review mechanisms that drive conversion of somatic cells to iPS cells and the strategies adopted to circumvent integrative viral strategies. Finally, we discuss practical, ethical and legal considerations that require addressing before iPS cells can realize their potential as patient-specific cells for treatment of degenerative disease.
早期发育基因Oct4和Sox2的前病毒表达，与cMyc和Klf4或Nanog和Lin28协同作用，可诱导分化细胞呈现出与胚胎干细胞难以区分的多能性形态和功能特征。这些细胞被称为诱导多能干细胞（iPS细胞），在小鼠中，这些细胞的多能性通过基因/表面抗原表达的改变、表观基因组的重塑、囊胚注射后对胚胎谱系的贡献能力以及在畸胎瘤和活产嵌合体中向所有三个胚层的分化得以证实。重要的是，iPS细胞的体外定向分化可产生能够治疗人源化疾病小鼠模型的细胞。尽管取得了这些令人瞩目的结果，但iPS细胞的转化效率却低得令人沮丧。此外，整合病毒方法固有的对宿主细胞基因组造成的不可预测和随机的诱变，继续阻碍这些细胞在治疗环境中的应用。这引发了对生成iPS细胞的非整合策略的探索。在这里，我们综述了驱动体细胞转化为iPS细胞的机制以及为规避整合病毒策略而采用的策略。最后，我们讨论了在iPS细胞能够发挥其作为治疗退行性疾病的患者特异性细胞的潜力之前需要解决的实际、伦理和法律问题。
