美國斯坦福大學(xué)醫(yī)學(xué)院研究人員27日宣布，他們在實驗中繞過誘導(dǎo)多能干細胞(iPS)這一步驟,，首次直接將實驗鼠皮膚細胞轉(zhuǎn)化為神經(jīng)細胞,。這項成果對理解細胞分化及再生醫(yī)學(xué)研究均具有重要意義。
研究人員首先選擇了19個與細胞重組或神經(jīng)發(fā)展有關(guān)的基因,，然后利用慢病毒將這些基因植入來自實驗鼠胚胎的皮膚細胞中,。32天后，其中一些皮膚細胞開始向神經(jīng)細胞轉(zhuǎn)化,。研究人員隨后篩選出3個基因,，并再次利用慢病毒將其植入來自成年實驗鼠尾部的皮膚細胞。一周內(nèi),，約20％的實驗鼠皮膚細胞轉(zhuǎn)化為神經(jīng)細胞,。這些神經(jīng)細胞不但可以表達神經(jīng)蛋白，而且可與實驗室中的其他神經(jīng)細胞形成突觸,。
“我們對轉(zhuǎn)化的時間和效率感到驚訝,，”領(lǐng)導(dǎo)這項研究的斯坦福大學(xué)醫(yī)學(xué)院助理教授馬里厄斯·韋尼希說，“這比先轉(zhuǎn)化為誘導(dǎo)多能干細胞的步驟簡單多了,。”
誘導(dǎo)多能干細胞指經(jīng)過基因“重新編排”回歸到胚胎干細胞的狀態(tài),，從而具有類似胚胎干細胞分化能力的體細胞，其轉(zhuǎn)化為特定功能的細胞一般需要數(shù)周,，轉(zhuǎn)化率一般在1％至2％之間,。科學(xué)界此前普遍認為，將皮膚細胞轉(zhuǎn)化為其他體細胞必然要經(jīng)過誘導(dǎo)多能干細胞階段,，該領(lǐng)域的研究也是近年來的科研熱點之一,。
韋尼希認為，他們的研究表明,，多功能階段可能只是細胞的多種狀態(tài)之一,，而并非皮膚細胞轉(zhuǎn)化為其他細胞的必經(jīng)之路。找到可以誘導(dǎo)皮膚細胞向其他細胞轉(zhuǎn)化的基因組合對理解細胞分化及再生醫(yī)學(xué)研究均具有重要意義,。
這項研究成果27日發(fā)表在《自然》雜志網(wǎng)絡(luò)版上,。該研究目前尚處于動物研究階段，不過研究人員已決定將利用人類皮膚細胞開展類似研究,。（生物谷Bioon.com）
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Nature：細胞系間的強行改變
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Nature advance online publication 27 January 2010 | doi:10.1038/nature08797
Direct conversion of fibroblasts to functional neurons by defined factors
Thomas Vierbuchen1,2, Austin Ostermeier1,2, Zhiping P. Pang3, Yuko Kokubu1, Thomas C. Südhof3,4 & Marius Wernig1,2
1 Institute for Stem Cell Biology and Regenerative Medicine, Department of Pathology,
epartment of Molecular and Cellular Physiology,
2 Howard Hughes Medical Institute, Stanford University School of Medicine, 1050 Arastradero Road, Palo Alto, California 94304, USA
3 Correspondence to: Marius Wernig1,2 Correspondence and requests for materials should be addressed to M.W.
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.
