Institute for Stem Cell Biology and Regenerative Medicine, Department of Pathology, Stanford University School of Medicine, 1050 Arastradero Road, Palo Alto, California 94304, USA.
Nature. 2010 Feb 25;463(7284):1035-41. doi: 10.1038/nature08797. Epub 2010 Jan 27.
Cellular differentiation and lineage commitment are considered to be robust and irreversible processes during development. Recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. This raised the question of whether transcription factors could directly induce other defined somatic cell fates, and not only an undifferentiated state. We hypothesized that combinatorial expression of neural-lineage-specific transcription factors could directly convert fibroblasts into neurons. Starting from a pool of nineteen candidate genes, we identified a combination of only three factors, Ascl1, Brn2 (also called Pou3f2) and Myt1l, that suffice to rapidly and efficiently convert mouse embryonic and postnatal fibroblasts into functional neurons in vitro. These induced neuronal (iN) cells express multiple neuron-specific proteins, generate action potentials and form functional synapses. Generation of iN cells from non-neural lineages could have important implications for studies of neural development, neurological disease modelling and regenerative medicine.
细胞分化和谱系决定被认为是发育过程中稳健且不可逆的过程。最近的研究表明，通过组合使用四种转录因子，小鼠和人类成纤维细胞可以被重编程为多能状态。这就提出了一个问题，即转录因子是否可以直接诱导其他定义明确的体细胞命运，而不仅仅是未分化状态。我们假设，神经谱系特异性转录因子的组合表达可以直接将成纤维细胞转化为神经元。从一组 19 个候选基因开始，我们仅鉴定出了三种因子的组合，即 Ascl1、Brn2（也称为 Pou3f2）和 Myt1l，这足以快速有效地将小鼠胚胎和成体成纤维细胞在体外转化为功能性神经元。这些诱导的神经元（iN）细胞表达多种神经元特异性蛋白，产生动作电位并形成功能性突触。从非神经谱系中产生 iN 细胞可能对神经发育研究、神经疾病建模和再生医学具有重要意义。
