Science：用老年ALS患者皮肤制造iPS细胞

图片说明：病患特异性的星形细胞。

（图片来源：Kit Rodolfa和哈佛大学的John Dimos）

据7月31日的《科学》（Science）杂志报道说，研究人员朝着应用诱导多能干细胞（或称“iPS”细胞）来治疗疾病的目标又迈出了重要的一步。研究人员从来自2位罹患肌萎缩性脊髓侧索硬化症（ALS）这种神经退行性病变的老年病人的皮肤采样中制造出了iPS。而且，他们用这些iPS 细胞发展出了看来像是健康的运动神经元细胞。较早的研究显示，iPS 细胞就像是多能胚胎干细胞那样可以演变为多种类型的细胞，而这些iPS 可以从健康的捐赠者的细胞中产生。但是，这种技术是否也适用于来自罹患慢性疾病的老年人则仍然是一个悬而未决的问题。

John Dimos 及其同事开始对来自两位罹患遗传形式的ALS 病患的皮肤细胞进行实验，并通过加入四种基因将这些细胞转变回iPS 细胞，而这四种基因是研究人员先前用来将细胞程序进行重新设定使其演变为iPS 状态的基因。接着，研究人员将来自其中一名病患的iPS 细胞沉浸在多种信号分子中，设法使这些细胞成为看上去像是运动神经元的细胞，而运动神经元是在ALS 中遭损害的细胞。这一做法的终极希望是：用像这样的iPS 来制造在遗传上相匹配的健康细胞，并用其取代病变的细胞。但是，在将这种方法安全地用于人身上之前，仍然还有重大的障碍需要克服。与此同时，病患特异性的iPS 细胞将是研究ALS 样疾病发生机理的重要工具。在大多数的情况下，ALS是遗传与环境因子间复杂的相互作用的结果，这使得在细胞培养中来研究这种疾病变得非常困难。但是，来自有遗传变异（这些变异使得变异基因携带者容易罹患该种疾病）的病人的iPS 细胞则恰好携带着个体病人中与该疾病有关的“众多”的遗传信息。

原始出处：

Science，DOI: 10.1126/science.1158799，John T. Dimos，Kevin Eggan

Induced Pluripotent Stem Cells Generated from Patients with ALS Can Be Differentiated into Motor Neurons

John T. Dimos ¹, Kit T. Rodolfa ², Kathy K. Niakan ¹, Laurin M. Weisenthal ¹, Hiroshi Mitsumoto ³, Wendy Chung ⁴, Gist F. Croft ⁵, Genevieve Saphier ¹, Rudy Leibel ⁶, Robin Goland ⁷, Hynek Wichterle ⁵, Christopher E. Henderson ⁵, Kevin Eggan ^1*

¹ Harvard Stem Cell Institute, Stowers Medical Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
² Harvard Stem Cell Institute, Stowers Medical Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
³ Eleanor and Lou Gehrig MDA-ALS Research Center, Neurological Institute, Columbia University Medical Center, New York, NY 10032, USA.; Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032, USA.
⁴ Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032, USA.; Division of Molecular Genetics and Naomi Barrie Diabetes Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
⁵ Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032, USA.; Departments of Pathology, Neurology and Neuroscience, Columbia University Medical Center, New York, NY 10032, USA.
⁶ Division of Molecular Genetics and Naomi Barrie Diabetes Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
⁷ Department of Medicine and Naomi Barrie Diabetes Center, Columbia University Medical Center, New York, NY 10032, USA.

^* To whom correspondence should be addressed.
Kevin Eggan , E-mail: eggan@mcb.harvard.edu

These authors contributed equally to this work.

The generation of pluripotent stem cells from an individual patient would enable the large-scale production of the cell-types affected by that patient’s disease. These cells could in turn be used for disease modeling, drug discovery, and eventually autologous cell-replacement therapies. Although recent studies have demonstrated the reprogramming of human fibroblasts to a pluripotent state, it remains unclear whether these induced pluripotent stem (iPS) cells can be produced directly from elderly patients with chronic disease. We have generated iPS cells from an 82-year-old woman diagnosed with a familial form of amyotrophic lateral sclerosis (ALS). These patient-specific iPS cells possess properties of embryonic stem cells and were successfully directed to differentiate into motor neurons, the cell type destroyed in ALS.