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本帖最后由 细胞海洋 于 2011-1-13 06:48 编辑
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' ]. N8 j: z C; O/ W加州大学圣地亚哥分校医学院及斯克里普斯研究所的干细胞科学家领导的跨国研究团队，记录了在人类胚胎干细胞(hESC)和诱导功能干细胞(iPSC)系中特殊的基因畸变，题为《在细胞重组和培养过程中人类胚胎干细胞和诱导多功能干细胞的细胞增殖和全能性的拷贝数量上的动态变化》已在1月7日的Cell Stem Cell上发表。该公布的发现强调了需要对多能干细胞进行频繁的基因检测以保证其稳定性和临床安全性。1 n( M2 p# q8 e+ }) q
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该研究的第一作者，加州大学圣地亚哥分校再生医学系的路易斯.劳伦特博士认为，我们发现人类多能干细胞(hESC和iPSC)比其他类型细胞有更高的基因畸变的频率。最令人吃惊的是，与其他非多能干细胞样本相比较，我们观察到hESCs的基因扩增和iPSC的缺失方面出现的频率更高。
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" Y4 ]! p6 T _ C' e |人类多能干笑细胞在人体内具有发展成其他类型细胞的能力，可称为细胞替换治疗的潜在来源。斯克里普斯研究员再生医学中心主任，珍妮.罗伦教授谈到，由于基因畸变常常与癌症相关联，免受癌症相关的基因突变对于临床使用的细胞系来说至关重要。
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研究团队确认了在多能干细胞系中可能发生突变的基因区域。对于hESC而言，可观察到的畸变大多是靠近多潜能相关基因区域的基因扩增；对于iPSC而言，扩增主要涉及细胞增殖基因及与肿瘤抑制基因相关的缺失。传统的显微技术，如染色体组型分析可能无法检测到这些变化。研究组使用一种高分辨率的分子技术，称为"单核苷酸多态性(SNP)"，能观察到人类基因组里一百多万个位点里的基因变化。5 m! {/ ~7 R" M& Q3 z7 D6 m
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劳伦说，我们惊喜地发现在较短时间培养中的基因变化，例如在体细胞重编程为多能干细胞的过程以及在培养中细胞的分化过程。我们不知道这会有怎样的影响，如果有的话，这些基因畸变都会对基础研究或者临床应用的结果产生影响，对此应当深究。
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) `3 r4 J& g$ }0 w2 b$ d劳伦总结到，该研究结果解释了有必要对多能干细胞培养进行经常性的基因监控，SNP分析仍不失人类胚胎干细胞和多能干细胞日常监控的一部分，但是这一结果提醒我们应当予以重视。（生物谷Bioon.com）% _' n/ i; j) E2 {6 C' ~
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原文链接：http://www.medicalnewstoday.com/articles/213047.php
# f0 ^3 |; |/ w1 O, V% h译文链接：http://www.chinastemcell.org/page/zixun_xwdtlist.aspx?infoid=970
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生物谷推荐英文摘要：5 `% [$ Q% B# k) ]/ H; ~
8 n4 W6 Q# ]3 S# N0 l# K) S7 y# VCell Stem Cell doi：10.1016/j.stem.2010.12.0033 E9 `0 X' H1 s! d, {
- ~. J9 m( _/ e% O$ ?9 ]* {8 tDynamic Changes in the Copy Number of Pluripotency and Cell Proliferation Genes in Human ESCs and iPSCs during Reprogramming and Time in Culture$ D4 Z' n; N _# f4 n+ k
Louise C. Laurent, Igor Ulitsky, Ileana Slavin, Ha Tran, Andrew Schork, Robert Morey, Candace Lynch, Julie V. Harness, Sunray Lee, Maria J. Barrero, Sherman Ku, Marina Martynova, Ruslan Semechkin, Vasiliy Galat, Joel Gottesfeld, Juan Carlos Izpisua Belmonte, Chuck Murry, Hans S. Keirstead, Hyun-Sook Park, Uli Schmidt, Andrew L. Laslett, Franz-Josef Muller, Caroline M. Nievergelt, Ron Shamir, Jeanne F. Loring' H0 o4 O$ J4 t/ j; U/ B
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The tremendous self-renewal and differentiation capabilities of human pluripotent stem cells (hPSCs) make them potential sources of differentiated cells for cell therapy. Cell therapies are subject to rigorous safety trials, and high priority is placed on demonstrating that the cells are nontumorigenic (Fox, 2008). Because genetic aberrations have been strongly associated with cancers, it is important that preparations destined for clinical use are free from cancer-associated genomic alterations. Human embryonic stem cell (hESC) lines have been shown to become aneuploid in culture (Baker et al., 2007,Draper et al., 2004,Imreh et al., 2006,Maitra et al., 2005,Mitalipova et al., 2005), and the most frequent changes, trisomies of chromosomes 12 and 17, are also characteristic of malignant germ cell tumors (Atkin and Baker, 1982,Rodriguez et al., 1993,Skotheim et al., 2002). Aneuploidies can be detected by karyotyping, but less easily detectable subchromosomal genetic changes may also have adverse effects. Small abnormalities have been detected in hESCs by using comparative genomic hybridization (CGH) and single-nucleotide polymorphism (SNP) genotyping (Lefort et al., 2008,N?rv? et al., 2010,Spits et al., 2008). These studies lacked sufficient resolution and power to identify cell type-associated duplications and deletions. A recent study has reported the use of gene expression data to detect genomic aberrations in a large number of hESCs and hiPSCs (Mayshar et al., 2010). However, the methods used could reliably detect only relatively large (≥10 megabase) aberrations, and the lack of nonpluripotent samples for comparison precluded the authors from determining which regions of genomic aberration were specific to pluripotent stem cells.
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In this study, we performed high-resolution SNP genotyping on a large number of hESC lines, induced human pluripotent stem cell lines (hiPSCs), somatic stem cells, primary cells, and tissues. We found that hESC lines had a higher frequency of genomic aberrations compared to the other cell types. Furthermore, we identified regions in the genome that had a greater tendency to be aberrant in the hESCs when compared to the other cell types examined. Recurrent regions of duplication were seen on chromosome 12, encompassing the pluripotency-associated transcription factor NANOG and a nearby NANOG pseudogene, and on chromosome 20, upstream of the DNA methyltransferase DNMT3B. Although the frequency of genomic aberrations seen in the hiPSC lines was similar to those of cultured somatic cells and tissues, we observed one of the recurrent areas of duplication characteristic of hESCs in one of the hiPSC lines.4 X4 F. |5 V" q: ^ V3 d6 p
/ ]' H' U' Y5 t* JFurthermore, comparison of 12 hiPSC lines generated from the same primary fibroblast cell line identified genomic aberrations that were present in the hiPSC lines and absent from the original fibroblast line. Analysis of early- and late-passage samples from these hiPSC lines allowed us to distinguish between events that arose during the process of reprogramming and those that accumulated during long-term passage. In general, deletions tended to occur with reprogramming and involve tumor-suppressor genes, whereas duplications accumulated with passaging and tended to encompass tumor-promoting genes. These results suggest that human pluripotent stem cell populations are prone to genomic aberrations that could compromise their stability and utility for clinical applications and that reprogramming and expansion in culture may lead to selection for particular genomic changes.' \: Y; i$ F0 E( h
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海洋注：3楼原文 感谢ydj19830提供 |
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发表于 2011-1-12 20:06
