oct4-induced reprogramming is required for adult brain neural stem cell differentiation into midbrain dopaminergic neuronsoct4-induced重组需要成人的大脑神经干细胞分化成中脑多巴胺能神经元.pdfVIP

Oct4-Induced Reprogramming Is Required for Adult Brain Neural Stem Cell Differentiation into Midbrain Dopaminergic Neurons Michela Deleidi1,2, Oliver Cooper 1,2, Gunnar Hargus1,2, Adam Levy1,2, Ole Isacson 1,2* 1 Center for Neuroregeneration Research, Harvard Medical School/McLean Hospital, Belmont, Massachusetts, United States of America, 2 Udall Parkinson’s Disease Research Center of Excellence, Harvard Medical School, Boston, Massachusetts, United States of America Abstract Neural stem cells (NSCs) lose their competency to generate region-specific neuronal populations at an early stage during embryonic brain development. Here we investigated whether epigenetic modifications can reverse the regional restriction of mouse adult brain subventricular zone (SVZ) NSCs. Using a variety of chemicals that interfere with DNA methylation and histone acetylation, we showed that such epigenetic modifications increased neuronal differentiation but did not enable specific regional patterning, such as midbrain dopaminergic (DA) neuron generation. Only after Oct-4 overexpression did adult NSCs acquire a pluripotent state that allowed differentiation into midbrain DA neurons. DA neurons derived from Oct4-reprogrammed NSCs improved behavioural motor deficits in a rat model of Parkinson’s disease (PD) upon intrastriatal transplantation. Here we report for the first time the successful differentiation of SVZ adult NSCs into functional region- specific midbrain DA neurons, by means of Oct-4 induced pluripotency. Citation: Deleidi M, Cooper O, Hargus G, Levy A, Isacson O (2011) Oct4-Induced Reprogramming Is Required for Adult Brain Neural Stem Cell Differentiation into Midbrain Dopaminergic Neurons. PLoS ONE 6(5): e19926. doi:10.1371/journal.pone.0019926 Editor: Jialin Charles Zheng, University of Nebraska Medical Center, United States of America Received October 26, 2010; Accepte