越来越不“给力”的iPS细胞

marrowstem

       最近几年，iPS细胞风生水起，一直处于生命科学研究的潮头，是引领干细胞研究的桥头堡。原因是他有胚胎干细胞所无法比拟的优势，因为他是来自成体细胞被重编程后的胚胎样干细胞，可以绕过胚胎干细胞所无法绕过的免疫排斥障碍和研究中的伦理障碍，所以是医学研究人员最寄予厚望的再生医学原材料，另外iPS细胞的产生也证明了一点——即在细胞水平，“返老还童”是可以人为做到的。
7 F5 F! a2 q$ e0 C2 E    但从去年开始，iPS细胞的这些优势似乎正在一点点消失殆尽。首先是转分化研究的步步兴起，到目前为止已有三篇paper连续证明一些体细胞可以直接转分化为另一种类的成体细胞，而且这种细胞重编程过程不需要经过iPS细胞所需经历的逆分化转录过程，所以比iPS细胞来的更直接和更安全。
7 ?2 Y+ f* \0 {! t. M$ b     此外也是在去年开始，有研究人员发现，与胚胎干细胞相比，iPS细胞存在更多的“隐患”，有更高的致癌性。另外通过大规模的“基因扫描”，发现iPS细胞和ES细胞在基因表达和表观上也存在很大的不同，并证明iPS细胞can't forget their past，并不是完整意义上的embryonic-like stemness cells。
$ Y  U0 N7 q" E8 U+ b    不知大家有没有注意到，在2010后半程+2011的前半程，这些否定iPS细胞优势的paper有井喷之势。最近《自然》也来凑这摊子热闹，发表了一篇名为：Flaw in induced-stem-cell model的评论性文章，副标题是：Adult cells do not fully convert to embryonic-like state.. ?: K( h9 C' t$ ^! t
而我们知道，《自然》杂志一直是发表和推崇iPS细胞的最“热心”杂志，对iPS细胞的态度，《自然》也显得越来越不自然了。. X1 u. d' d5 X
    因此个人感觉iPS细胞目前是四面楚歌，这四面是iPS细胞的致癌性，iPS细胞的不完全stemness性，iPS细胞的原组织印迹性和他的重编程机制不明确性。iPS细胞到底何去何从，让我们拭目以待。3 A8 \/ P4 `, |# B4 ?% u* i: \# Q

marrowstem

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& J3 F% I% b6 P. I9 DFlaw in induced-stem-cell model
' H) m6 e. {, M. \$ }5 ]7 t: ?3 jAdult cells do not fully convert to embryonic-like state.
  B5 ]: [1 J2 `# a% dElie Dolgin
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      Medical researchers' hopes of replacing politically fraught embryonic stem (ES) cells with stem cells derived from adult tissues have suffered a setback. Induced pluripotent stem (iPS) cells, created by turning back the developmental clock on adult tissues, and ES cells display similar gene-expression patterns, and both can produce any of the various tissues in the human body. But patterns of epigenetic changes — alterations that affect gene expression without changing the DNA sequence — tell a different story about iPS cells, a team led by Joseph Ecker, a molecular geneticist at the Salk Institute in La Jolla, California, reports online in Nature this week1.
9 n% T" c6 Z" M7 D       "They are slightly different creatures," says Chad Cowan, a stem-cell biologist at Massachusetts General Hospital in Boston who was not involved in the work. The finding suggests that iPS cells may not be suitable substitutes for ES cells in modelling or treating disease.: I7 e# H) ^, N& Z2 |9 g
      Ecker and his colleagues analysed patterns of DNA methylation, a type of epigenetic change, across the genomes of 15 cell lines. These included four human ES cell lines, five iPS cell lines and the tissues from which they came, as well as differentiated cells made from both kinds of stem cells. "If you look with blinders on, they look fairly similar," says Ecker. "But if you zoom in you find different signatures of what an iPS cell is."
9 o, g5 g/ `! d( {6 a    The researchers found that rather than being reset to an embryo-like state, methylation patterns near the tips and centres of chromosomes in the iPS cells resembled those in the adult tissues from which the iPS cells had been derived. This could constrain the types of tissues that the cells are capable of forming. "The reprogramming process, although fascinating, is a fundamentally different way of getting to pluripotency than deriving cells from [embryos]," says George Daley, a stem-cell expert at Children's Hospital Boston in Massachusetts. "We're still looking for reprogramming methods that return cells to the ES-cell-like state," he adds.9 ^/ K1 I0 M: m/ f
       The finding that reprogrammed stem cells carry an epigenetic 'memory' dovetails with work published last year by Daley and others comparing mouse iPS and ES cells2,3. In mice, however, the methylation differences could be reset, either by continuing to culture the iPS cells or by differentiating the cells again to more specialized cell types. In the human cells, the epigenetic marks lingered even after the iPS cells had been coaxed to form new tissues., C+ d1 q: N2 L% e# S8 p! z
        Regardless of their epigenetic differences, neither iPS cells nor ES cells may turn out to be perfect models of tissues in the body. Both cell types seem to harbour genomic abnormalities. In separate work published last month4, a team led by Jeanne Loring, a stem-cell researcher at the Scripps Research Institute in La Jolla, found that ES cells tended to contain duplicated chunks of DNA linked to genes associated with self-renewal, whereas iPS cells incorporated extra cancer-causing genes and fewer tumour-suppressor genes. These genomic differences between the two types of stem cells probably result from the culturing techniques used to derive and maintain them.
5 Z7 U1 t9 n+ J4 Z4 [     "When we culture cells outside a normal organism they can acquire features that may not be compatible with life once they go back into an organism," says Richard Young, a stem-cell biologist at the Whitehead Institute in Cambridge, Massachusetts.
( L! J# H8 {7 e$ e       The impact of such discrepancies remain unclear, says William Lowry, a stem-cell biologist at the University of California, Los Angeles. "The problem is that we don't know if any of these differences are going to be consequential."
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Lister, R. et al. Nature doi:10.1038/nature09798 (2011).
$ m9 j7 K' K9 x  D$ v1 DKim, K. et al. Nature 467, 285-290 (2010). | Article | PubMed | ISI | OpenURL | | ChemPort |
* L0 e! N0 b+ g$ x; jPolo, J. M. et al. Nature Biotechnol. 28, 848-855 (2010). | Article | OpenURL   Q1 x% W  G& r" v' S7 X! G
Laurent, L. C. et al. Cell Stem Cell 8, 106-118 (2011). | Article | PubMed | OpenURL | | ChemPort

张也行

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marrowstem版主新年好！
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1 E; V; E  E6 a# k( r不太同意你的观点，iPS细胞是没有像以前前两年那么热了，但现在的iPS细胞的研究也越来越实际，也反映了人们对iPS细胞的期待也越来越高。正是在这样的背景下，iPS的研究才像现在这样深入，就像"Flaw in induced-stem-cell model"中Professor Ecker说的我们的研究越来越"zoom in"了。这时我们才看到iPS细胞和ES细胞还是有很大差异的，表观遗传上的memory成为iPS更突出的问题。想要解决问题首先要发现问题，现在问题出现了，相信以后就会有人解决这个问题。这总比临床上出现了问题之后才认识到这些问题要好得多吧。0 q* `9 R7 M1 w$ s) \- x
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以前大家一致认为iPS的主要问题是病毒载体带来的插入突变以及致癌基因，但是现在各种非插入型的载体已经应用于获得iPS细胞，reprogramming cocktail中的致癌基因也可以被替换或去除。更令人振奋的是去年用mRNA诱导iPS的成功，丁盛教授也用小分子替代了三个重编程因子，很可能未来Oct4也被小分子替换，（或者用mRNA和小分子结合的方法诱导），所以iPS还是在不断前进的。Nature杂志还是很有责任感的。
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iPS细胞还是很“给力”的！呵呵

tpwang

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张也行 发表于 2011-2-8 23:04
) v- E1 f/ w( i" h! X7 y: ~. rmarrowstem版主新年好！0 Q! s: \' M9 u9 N

1 [5 s' y4 M- k6 ^( r! C% r5 P7 K不太同意你的观点，iPS细胞是没有像以前前两年那么热了，但现在的iPS细胞的研究 ...

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' F/ c3 p* E4 l! g$ p基本同意。; F- _, ~( g! {+ A
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最新研究揭示的iPS倾向于导致“抑癌基因”的抑制，如果这种现象是采用外源性致癌因子所致，那么消除致癌因子，甚至采用非integrate方法得来的iPS应该没有这个问题。但如果采用RNA，小分子的方法得来的iPS还具有上述倾向性，那么问题就不简单是外源性致癌因子的问题，而是从成熟分化到胚胎状态的reprogramming本身具有的内在风险。那么问题就不那么简单了。' L8 r/ F) e" M. {/ `! u
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还没看到原文。但个人感觉这种可能性还是存在的。
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人iPS带有源细胞记忆的问题，如果确实是epigenetic的过程不完善所致，那么技术上应该可以能够改进到满意的程度吧。可能还是个培养条件的问题，小鼠的iPS传代后即有可能消除这种记忆，是个旁证。但这类研究建议应该对iPS的过程严密监视基因与表观遗传特性，这对iPS的普及与应用也带来一定的负担与限制，这是个操作性问题。
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即使克服了这些问题，iPS最终的可用性，确实要接受其他干细胞种类的挑战，尤其是直接转分化，如果能证明这个现象的确是普适性规律性的东西，那就很大程度上削弱了iPS的动力，起码从应用的角度。它还是自体来源，少了一大道工序，甚至可能少的不仅是工序，而是一个风险较大的弯弯绕，少了弯弯，风险也就相应少了。概念也容易讲清楚。
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直接转分化的进展，可能还会从另一个侧面推进成体干细胞的研发。从iPS的经验来看，如果用成体干细胞或progenitor之类来转分化，肯定效率更高。7 y7 _! G$ S6 Z! [7 t9 g6 E. b8 H* k

3 e6 @5 L- I9 x# IiPS的重编程价值，在其他方面也有体现。只要不是最终证明与癌干细胞双胞胎就可以了。
3 i* @# [- T) A# u6 P& T7 T  c楼主的担忧主要也在这方面。/ T/ @8 L' q/ C# E1 A. W0 I6 x
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希望不要是最坏的结局，干细胞多一个武器和途径一定是好的，无论是在研究上还是在应用上。1 R& Q( m, K+ d
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yangel

回复 marrowstem 的帖子
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对于质疑iPS性质的言论，我一直这么想，会不会是被研究的iPS细胞系的性质还不够好。
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大家也知道，同一批iPS诱导过程中出现的每个iPS cell colony的重编程阶段不一样，被诱导的性质也确实不太一样，所处的pluripotent state也可能不一样。因此，每个分离得到的iPS细胞系自然会有性质的差异，可能大多数还不是completely reprogrammed cells，有些因为“记忆”未被擦去，或者其它基因未正常表达，甚至完全进不了fully reprogramming的状态。
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" `( P& D" J, b( G. m% S是不是那些“没有进入状态”的iPS细胞系和ESC相比才有epigenetic状态的一些明显差异。是不是真正fully rperogrammed cells才和ESC的状态高度一致呢？我也建议周琪和高绍荣实验室的同志们，你们手里有能做四倍体聚合的细胞系，可以和其它细胞系比较一下，看看是不是这么回事儿。
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* x+ r. x# O/ N! y- M% {4 e如果确实fully reprogrammed iPSC也有些“问题”的话，我也还在想，是不是诱导iPS的基因或者小分子组合什么的都还不够优化，能否有一种办法可以诱导出没有乱七八糟记忆和“隐患”的iPS细胞系来呢。这也是iPS领域的一个潜在的方向吧。
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6 x& M7 H3 i: j- a: o! p6 v5 @3 H困难不是障碍，困难是前进的方向！3 T; x1 C7 G$ H# S6 ]+ Z& m/ Q

tpwang

yangel 发表于 2011-2-9 10:28 ! H9 b+ ]" p# |8 R$ @% h# t  r, l9 F
回复 marrowstem 的帖子7 i( H0 A# K5 n0 t! t1 n+ c
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对于质疑iPS性质的言论，我一直这么想，会不会是被研究的iPS细胞系的性质还不够好 ...

: @" }) z/ b& @* F- v. r1 uiPS重编程的技术问题应该可以设法解决，起码可以考虑解决。5 E( K! W# B/ Y/ H0 C  y4 Q& W
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iPS的根本问题是它所体现出的“重编程”机制是什么，用效率低下的例子来复述这个问题，即为什么效率低下，包括重编程“不完善”。一种理论说是有一部分细胞本身具备重编程潜能，看到的iPS是这部分细胞的结果，这个假设被称为“elite”模式，也就是说有一部分“优等”可重编程细胞。另一种理论认为，所有细胞的重编程潜能都一样，但在操作过程中，一小部分“不知为何”走上重编程道路，而其他没有。这个模式被称为“stochastic”理论。其实，这后一个理论还不能叫真正意义上的“理论”，只是解释现有iPS效率问题的一个假设。不管是哪种理论，只要这个重编程现象存在，逻辑上就应该有它的内在机制，或者已现在分子细胞生物学愿意的说法，就应该有分子水平的内在机制，或者只是有这种潜能，需要人为找出外在释放这种潜能的分子水平机制。
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/ S# a- p1 D' D8 p# I从这个意义上来说，iPS还是个没有理论的“现象”。有很多问题，也就不奇怪了。

Yedan

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7 `  h, s* _6 b% ~9 B5 C首先，先说说你们谈到的direct conversion，也就是转分化，是的，已经有neuron，blood progenitor和cardiomyocyst三类细胞的paper出来了，退一步说即使有普适性了，但是人体200多种细胞，难道每种细胞都这样做吗？转化医学的目标是要器官移植，当然iPS这方面建树也很少，但是体外器官的形成是模拟的胚胎发育，代替ES，这是iPS的优势，direct conversion做不到。如果是移植细胞，当我没说。
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其次，LZ一开始提到的“有研究人员发现，与胚胎干细胞相比，iPS细胞存在更多的“隐患”，有更高的致癌性。另外通过大规模的“基因扫描”，发现iPS细胞和ES细胞在基因表达和表观上也存在很大的不同，并证明iPS细胞can't forget their past，并不是完整意义上的embryonic-like stemness cells。”我不知道的这是那篇文献提出的，请明示。但是我没记错的话，去年6月份的Cell Stem Cell有一期，两篇Bioinformatics的文章专门对hiPS到底是不是embryonic-like stemness cells做了microarray，ChIP-seq等一系列分析，他们得出的结论原话是“Although some variation in chromatin structure and gene expression was observed in these cell lines , these variations did not serve to distinguish ESCs from iPSCs."。当然我们不能把话说得像他们那么绝对，说不定那些variations就和DD region的miRNAs一样造成那么大的影响，只是比较的hiPS，总不能打嵌合体人来说明吧。
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还有，关于小鼠iPS和ES的区别问题，其实我们没必要那么去care it，就拿我们实验室来说，做mouse就为了reprogramming的机制，往临床应用和致癌性问题上走，那是hiPS的事情，we don't care. 确实像前面几位说到的那样，我们做mouse的，拿Qi Zhou的4n细胞做标准就够solid了。但是在中国这个环境里打4n可不是那么容易的，（如果诸位有在美帝的，也当我没说），所以我们更多的是做出来的细胞打打chimera就OK了，不用那么纠结它到底跟mES有多像，因为我们不拿它去做转化医学，我们是去找reprogramming的机制的。如果非要很严谨的做，那我们每个实验室做的iPS都得先打4n，然后microarray和ChIP-seq挑一个做，跟ES去比比，这样做出来的iPS那是现在条件下最苛刻标准出来的了，但是那成本即使在美帝也没几个实验室能接受的。6 D% Y! c* k! c) v
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总结一句话，iPS的热潮没那么容易退下去，但是做它的要求会也来越高，标准也会越来越规范，越来越多。

marrowstem

Yedan 发表于 2011-2-9 16:00 - d$ {+ [- |% s2 a$ H8 K6 n4 ?2 I
首先，先说说你们谈到的direct conversion，也就是转分化，是的，已经有neuron，blood progenitor和cardiom ...

8 V" a0 ]/ x9 [# @      关于你所疑问的我所说的有关iPS细胞可能存在的几方面“缺陷”，我想关注细胞重编程研究的人都会说这么一句“你懂得！”，另外这些方面也是当前iPS细胞研究的一些热点：转分化、iPS细胞的“记忆性”和致癌性。我在第二贴中引用的这篇Nature的文章的副标题就有这个意思：Adult cells do not fully convert to embryonic-like state.
* c2 i) s* t9 J, [0 N% P# B   然后再允许我引用Nature的另一文：
1 @6 q- T/ g" o" S0 M        iU can't forget their past
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What's more, these incompletely or inadequately reprogrammed hotspots are maintained when iPS cells are differentiated into a more specialized cell type, providing what the researchers dubbed an iPS cell-specific signature. "We can tell by looking at these hotspots whether a cell is an iPS cell or an embryonic stem cell," says Ecker. "But we don't know yet what it means for their self-renewal or differentiation potential."
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! b, {" H& S& y6 g6 iTheir findings, published in the February 3, 2011, issue of Nature, confirm that iPS cells, which by all appearances look and act like embryonic stem cells, differ in certain aspects from their embryonic cousins, emphasizing that further research will be necessary before they can rightfully take embryonic stem cells' place.
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The fact that reprogramming of somatic (body) cells does not pose the same ethical quandaries as working with stem cells isolated from embryos prompted scientists to develop iPS technology for human cells that are just as potent as human embryonic stem cells, with the hope that one day, iPS cell technology can be applied to regenerative medicine.+ o1 @* A8 V. f) ]2 G" ]
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But before cells derived from iPS cells can be used to repair tissue damaged through disease or injury, some remaining questions have to be solved. "Embryonic stem cells are considered the gold standard for pluripotency," says Ecker. "So we need to know whether -- and if so, how -- iPS cells differ from ES cells.": r0 N( p  X4 r# e- y
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The reprogramming process, which turns back the clock and endows fully differentiated cells with pluripotent potential, is not a genetic transformation but an epigenomic one. The epigenome is what differentiates a fibroblast from a hepatocyte and a stem cell from a fully differentiated cell. With a few exceptions, every cell in our body contains the same genome, but epigenomic marks -- tiny tags atop DNA that can tell your genes to turn on or off, to speak up or speak softly -- determine a cell's gene expression profile and hence its fate.
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While others have compared genomic bits and pieces between iPS and embryonic stem cells -- and found small differences -- the Salk researchers and their collaborators at the University of Wisconsin and the University of California, San Diego, set their sights higher.* E+ |/ w( ?0 w6 z2 L

& H; O5 N/ o9 E1 lThey scrutinized whole-genome DNA methylation profiles -- methylation is one the best-studied and most important epigenetic tags -- at single-base resolution in five iPS cell lines, along with the methylomes of embryonic stem cells and somatic cells and differentiated iPS cells and differentiated embryonic stem cells.
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Reprogramming induces a remarkable wholesale reconfiguration of the DNA methylation pattern throughout the genome, returning partially methylated domains to a fully methylated state; reinstating so-called non-CG methylation; and reprogramming most unmethylated and methylated CG islands, which play a crucial role in regulation gene activity, to an embryonic stem cell-like state.
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"Overall, this process results in an iPS cell methylation pattern that's very similar to that of embryonic stem cells," says postdoctoral researcher and co-first author Ryan Lister. "But when we started to dig deeper, we discovered significant differences."
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Their experiments revealed considerable variability between iPS cell lines, including a "memory" of their tissue of origin. "Some marks carry over," explains Ecker. "If iPS cells were derived from adipose tissue, we can see that they "remember" some methylation marks from being a fat cell." Furthermore, new methylation patterns not found in either embryonic stem cells or the tissues of origin were identified in the iPS cells, and many of the regions showing epigenomic changes were disrupted in all iPS lines studied.9 r; j# i) @- y2 m  ^$ q, l1 M% {

% s2 \& f) K1 V8 V% x7 r0 J5 nBut regardless of their individual history, iPS cells showed a common defect -- hotspots near telomeres and centromeres that proved resistant to reprogramming. Averaging more than one million bases in length, these hotspots failed to acquire the non-CG methylation typical of embryonic stem cells.# u* F+ \# ?" n

( b7 [" D% H* `4 g"These regions are really signatures," explains postdoctoral researcher and co-first author Mattia Pelizzola. "They are shared in iPS cells derived from different parental cells, by different research groups and using different methodologies. Moreover, these regions coincide with specific modifications of histones -- proteins that are important to determine the accessibility and the activity of genomic regions -- and the genes contained within these regions are less expressed."# Y/ G0 E1 p+ g- E
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However, when the researchers zoomed in closer, they found that the opposite held true for CG islands, short stretches of CG-rich DNA sequences that are typically found in the proximity of genes, where they may regulate gene activity. "The consequence is that some genes within these areas seem to be silenced by the altered CG island methylation patterns in the iPS cells," says Lister. "Conceivably, these changes could limit the potential fate of the iPS cells."
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To gain a better understanding of the implications, they looked again at these regions after differentiating embryonic stem cells and iPS cells into trophoblasts, a standard cell differentiation assay. A subset of iPS cell-specific silencing marks were transmitted to differentiated cells at high frequency. "They are not easily removed," says Lister, "and could be used as a diagnostic marker for incomplete reprogramming."
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3 v2 W6 L4 Q' m; l8 }) P! yAdds Ecker: "Now that we know that these regions exist, we want to understand why these regions can't be reprogrammed to a more ES cell-like state."1 \# Z! D# G! F3 d/ x7 _

( r% Y$ z1 R! S" O$ ]Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature, 2011; DOI: 10.1038/nature09798 2 u, n. |, w5 }( {! z

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marrowstem

       机制不明的东东往往走不远，iPS细胞目前就处于这样一种现状，这一点有些象“水中捞月”，当你试图靠近他时，往往搅浑的是一池江水。% L0 `" F# i( R4 N
   另外我写此帖的目的也是想说明一点，iPS细胞并不是“完美无缺”的，他也有缺陷在里面可能隐藏。对一些很popular、赚人眼球的研究热点，我们往往需要给它泼点冷水、降降温，以免盲目而狂热的跟进，到头来却是“竹篮打水一场空”。为什么要这么说，因为科学最大的忌讳是人云也云，而推倒科学前进的动力则是质疑精神和批判性的接受的态度。
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tpwang

Yedan 发表于 2011-2-9 16:00 / n" y0 o* D+ S% r( T9 v! H+ J
首先，先说说你们谈到的direct conversion，也就是转分化，是的，已经有neuron，blood progenitor和cardiom ...

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楼主讨论的自然是iPS的终极标准问题，至于谁能做得起最严格标准的要求，那是另外一个问题。" H; p) _, s% V0 K# }
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另外通过大规模的“基因扫描”，发现iPS细胞和ES细胞在基因表达和表观上也存在很大的不同，并证明iPS细胞can't forget their past，并不是完整意义上的embryonic-like stemness cells。”我不知道的这是那篇文献提出的，请明示。这个去年以及今年刚发表的文章（楼主引用了Nature的评论里也特别指出了出处）都已经说明了的，基本是文献共识吧。( _) e4 C* J9 u! v6 m5 ^

6 ^/ n4 I  s" Q. _7 riPS用于疾病模拟和发育机制的研究自然是有不可替代的潜在价值（潜在价值，疾病模型问题也还不少），但iPS之所以如此“热”，则不是因为这两方面的潜力，而恰恰是作为”理想细胞来源“用于个体化的再生医学细胞治疗。所以，对iPS的一些疑问也主要是针对这一点而发的，而不是针对疾病模型和发育机制的平台作用。
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: v2 S7 \1 n' ]  u, w/ s直接转分化是否能成气候，确实还要看。可以绕过iPS理论上还是说得过去的。这也是说它的再生医学细胞治疗意义，而不是针对疾病模型和发育研究而说。6 b# y6 j* D' n! ^# s6 }4 {8 D1 Y4 u
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个人感觉你的疑问与楼主的说法并不太矛盾，只是关注了iPS的不同方面和意义。