Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Stem Cells. 2009 Dec;27(12):3053-62. doi: 10.1002/stem.242.
Direct reprogramming of differentiated cells to induced pluripotent stem (iPS) cells by ectopic expression of defined transcription factors (TFs) represents a significant breakthrough towards the use of stem cells in regenerative medicine (Takahashi and Yamanaka Cell 2006;126:663-676). However, the virus-mediated expression of exogenous transcription factors could be potentially harmful and, therefore, represents a barrier to the clinical use of iPS cells. Several approaches, ranging from plasmid-mediated TF expression to introduction of recombinant TFs (Yamanaka Cell 2009;137:13-17; Zhou, Wu, Joo et al. Cell Stem Cell 2009;4:381-384), have been reported to address the risk associated with viral integration. We describe an alternative strategy of reprogramming somatic progenitors entirely through the recruitment of endogenous genes without the introduction of genetic materials or exogenous factors. To this end, we reprogrammed accessible and renewable progenitors from the limbal epithelium of adult rat eye by microenvironment-based induction of endogenous iPS cell genes. Non cell-autonomous reprogramming generates cells that are pluripotent and capable of differentiating into functional neurons, cardiomyocytes, and hepatocytes, which may facilitate autologous cell therapy to treat degenerative diseases.
通过异位表达特定转录因子（TFs）将分化细胞直接重编程为诱导多能干细胞（iPS 细胞），这是再生医学中使用干细胞的重大突破（Takahashi 和 Yamanaka Cell 2006；126:663-676）。然而，病毒介导的外源性转录因子表达可能具有潜在的危害性，因此，这是 iPS 细胞临床应用的一个障碍。已经报道了几种方法，从质粒介导的 TF 表达到重组 TF 的引入（Yamanaka Cell 2009；137:13-17；Zhou、Wu、Joo 等人，Cell Stem Cell 2009；4:381-384），以解决与病毒整合相关的风险。我们描述了一种替代策略，即完全通过募集内源性基因来重编程体细胞祖细胞，而不引入遗传物质或外源性因素。为此，我们通过基于微环境的内源性 iPS 细胞基因诱导，从成年大鼠眼的角膜缘上皮中重编程可及且可再生的祖细胞。非细胞自主重编程产生的细胞具有多能性，并能够分化为功能性神经元、心肌细胞和成肝细胞，这可能有助于自体细胞疗法来治疗退行性疾病。
