Stadtfeld Matthias, Brennand Kristen, Hochedlinger Konrad
Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, 185 Cambridge Street, Boston, MA 02114, USA.
Curr Biol. 2008 Jun 24;18(12):890-4. doi: 10.1016/j.cub.2008.05.010. Epub 2008 May 22.
Induced pluripotent stem (iPS) cells have been derived from fibroblast, stomach, and liver cultures at extremely low frequencies by ectopic expression of the transcription factors Oct4, Sox2, c-myc, and Klf4, a process coined direct or in vitro reprogramming [1-8]. iPS cells are molecularly and functionally highly similar to embryonic stem cells (ESCs), including their ability to contribute to all tissues as well as the germline in mice. The heterogeneity of the starting cell populations and the low efficiency of reprogramming suggested that a rare cell type, such as an adult stem cell, might be the cell of origin for iPS cells and that differentiated cells are refractory to reprogramming. Here, we used inducible lentiviruses [9] to express Oct4, Sox2, c-myc, and Klf4 in pancreatic beta cells to assess whether a defined terminally differentiated cell type remains amenable to reprogramming. Genetically marked beta cells gave rise to iPS cells that expressed pluripotency markers, formed teratomas, and contributed to cell types of all germ layers in chimeric animals. Our results provide genetic proof that terminally differentiated cells can be reprogrammed into pluripotent cells, suggesting that in vitro reprogramming is not restricted to certain cell types or differentiation stages.
通过转录因子Oct4、Sox2、c - myc和Klf4的异位表达，已从成纤维细胞、胃和肝脏培养物中以极低频率获得诱导多能干细胞（iPS细胞），这一过程被称为直接重编程或体外重编程[1 - 8]。iPS细胞在分子和功能上与胚胎干细胞（ESC）高度相似，包括它们在小鼠中对所有组织以及生殖系的贡献能力。起始细胞群体的异质性和重编程的低效率表明，一种罕见的细胞类型，如成体干细胞，可能是iPS细胞的起源细胞，并且分化细胞对重编程具有抗性。在这里，我们使用可诱导慢病毒[9]在胰腺β细胞中表达Oct4、Sox2、c - myc和Klf4，以评估一种确定的终末分化细胞类型是否仍然易于重编程。基因标记的β细胞产生了表达多能性标志物、形成畸胎瘤并对嵌合动物中所有胚层的细胞类型有贡献的iPS细胞。我们的结果提供了遗传学证据，证明终末分化细胞可以被重编程为多能细胞，这表明体外重编程不限于某些细胞类型或分化阶段。
