ES与iPS的体外后代细胞发育不完善

sunsong7

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3 _+ u7 z; b- i! o6 ]1 ~' z加州洛杉矶分校研究人员发现，由人类胚胎干细胞和重编程干细胞培育出的三种类型分化细胞与直接来源于正常人体组织同型细胞相比，存在发育不完善的现象，更像是来自两个月以内的胎儿细胞，该发现也许对于胚胎发育学研究是一件令人兴奋的事情，但对于疾病模型建立无疑增加了新的挑战，除非该模型仅用于研究2个月以内的组织发生期疾病。
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' @' V4 O' ?5 ?1 W6 H: p. h0 ?Cells Derived from Pluripotent Stem Cells Are Developmentally Immature
" N% _( Y1 f- MScienceDaily (Aug. 18, 2011) — Stem cell researchers at UCLA have discovered that three types of cells derived from human embryonic stem cells and induced pluripotent stem cells are similar to each other, but are much more developmentally immature than previously thought when compared to those same cell types taken directly from human tissue.
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/ i. ^" w3 D; i- h6 e$ _8 J4 M% SThe researchers, from the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, found that the progeny of the human embryonic stem cells and induced pluripotent stem cells (iPS) were more similar to cells found within the first two months of fetal development than anything later. This could have implications both clinically and for disease modeling, said William Lowry, senior author of the study and an assistant professor of molecular, cell and developmental biology in the Life Sciences.
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' r6 {; Q2 P* l$ e7 L' q* `. uThe two-year study was published August 17 in the peer-reviewed journal Cell Research.
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4 D, Q# \, k. Y4 @  ?"Once we found that the human embryonic stem cell- and the iPS-derived progeny were similar, we wanted to understand how similar the progeny were to the same cells taken directly from human tissue," Lowry said. "What we found, looking at gene expression, was that the cells we derived were similar to cells found in early fetal development and were functionally much more immature than cells taken from human tissue. This finding may lead to exciting new ways to study early human development, but it also may present a challenge for transplantation, because the cells you end up with are not something that's indicative of a cell you'd find in an adult or even in a newborn baby."
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+ F$ L7 t  d! ^: D# ~, YThere might also be challenges in disease modeling, unless you're modeling diseases that occur within the first two months of development, Lowry said./ B: r1 I: K4 Y) ^- P
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Employing the most commonly used methods for deriving cells from embryonic stem cells and iPS cells, Lowry and his team differentiated these human pluripotent stem cells into neural progenitor cells, which create neurons and glia, hepatocytes, the main tissue found in the liver, and fibroblasts, common to the skin. They selected those cell types because they are easy to identify and are among the most commonly differentiated cells made from pluripotent stem cells. They also represent cell types found in the three germ layers, the endoderm, mesoderm and ectoderm, where the first cell fate decisions are made, Lowry said.$ y$ o/ Z, g8 T# h4 p

9 Z) p0 M( ]3 a' G! rThe progeny of the human pluripotent stem cells were compared to each other using their gene expression patterns, functionality and appearance. There was essentially little or no difference between them, Lowry said. Then the work began to compare them to equivalent cell types found in humans.# }6 \% F- ]4 b, F# V

* w4 N3 X) I: J5 L  P' [' V"One important reason to do this is to ensure that the cells we are creating in the Petri dish and potentially using for transplantation are truly analogous to the cells originally found in humans," said Michaela Patterson, first author of the study and a graduate student researcher. "Ideally, they should be a similar as possible."& @  D( }8 S4 b$ Q% q# _% C
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What the team found was that while the progeny were alike, they bore striking differences from the same cells found in humans when analyzing their gene expression. A significant number of genes, about 100, were differentially expressed in the cell types made from pluripotent stem cells, Lowry said.9 E" @* N' p+ b

1 P6 Q6 b) L; c  D# ~2 a( p& DAbout half of those differentially expressed genes are normally thought to be strictly expressed in pluripotent stem cells, which have the potential to differentiate into any cell of the three germ layers. Those genes had not been turned off even after the cell had differentiated into either a neural progenitor cell, hepatocyte or a fibroblast, Patterson said.' O6 p7 m% `% |3 A0 }) z  L9 \

8 b' U$ x, v6 _- Z& z$ q# H5 C"Previously, we assumed that all pluripotency genes get shut off right away, after the fetus begins developing," Patterson said. "We found that this is not the case, and in fact some of these genes remain expressed."
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2 |$ r, Y0 j# ?6 ^$ ?0 oThe differences in gene expression could be problematic, Lowry said, because some of these same differentially expressed genes in the progeny are genes that are expressed during cancer development. Also worrisome was their developmental maturity -- would they work correctly when transplanted into humans? As part of their study, the team left the differentiating cells in culture about a month longer to see if they would further mature, and there was some modest but statistically significant maturation. However, genetic discrepancies remained.
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These discrepancies could be critical, Patterson said, particularly in the hepatocytes. During fetal development, these cells express proteins that aid the metabolism of the fetus, a role they don't play later in adults.8 a1 h" `8 R# o  Q7 S, n$ D
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"The roles these cells play in the fetus and the adult are inherently different," she said. "It may be that the progeny, if transplanted into a human, would mature to the same levels as those found in the adult liver. We don't know."% q' {2 m) _8 Z+ |! l

  L4 q! w. b! u* GThe team then compared the progeny to cells from humans that were closer to the progeny's developmental maturity and found that the two types of cells were indeed becoming more similar in gene expression and functionality, Lowry said.
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7 [% {4 m9 \4 [( h( C: g( _" H0 sThe UCLA team is not the first to suggest that the progeny of human pluripotent stem cells reflect an early developmental immaturity. However, these data put a more precise window on their developmental age.7 o  [6 M: B; m# V

$ a, B* K5 \! \! K  E) SGoing forward, Lowry and his team are going to study the 100 genes being differentially expressed in the progeny to see if manipulating some or all of them results in the maturation of the cells." ]  z( I9 a9 q( x: X2 j

: E7 N+ S1 ]4 Z* V) p7 T/ r" O: U"These findings provide support for the idea that human pluripotent stem cells can serve as useful in vitro models of early human development, but also raise important issues for disease modeling and the clinical applications of their derivatives," the study states." t: a! W8 A7 F  P. ^7 b. J1 |

4 ~$ F: x# F9 z9 ~+ ^4 zThe study was funded in part by a seed grant and training grants from the California Institute of Regenerative Medicine, the Basil O'Connor Started Scholar Award and the Fuller Foundation.# u2 Z! F+ N$ D+ {; r
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http://www.sciencedaily.com/releases/2011/08/110817092227.htm

towersimper

回复 sunsong7 的帖子
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! p- v: z+ F  p$ G) T# H; M. q分享一下啊，呵呵。
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托斯卡纳教父

很有意义的研究，Lowry一直做得很好。其实，我还想知道直接转分化后的细胞与正常细胞的比较。

biovictor

这可是很有挑战性的，更加清楚地表明，细胞中的调控复杂程度还要更复杂一些，有可能细胞器的成熟或者细胞器的分化程度，对细胞整体具有一定的影响，在下拙见。

fguw

该文章应该说蛮有意思，不过，“However, when compared to a tissuederived
' @- f+ n) {  E; T& [3 ]) \counterpart, the progeny of both hESCs and hiPSCs maintained expression of a subset of genes normally associated with early mammalian development, regardless of the type of cell generated‘   我个人认为，体外诱导的过程无法模拟体内的过程，所以，自然有差异。 我觉得，如果用IPSC，HESC 做疾病模型，应该多花发功夫做体外诱导分化，作者文章似乎没有体现，欢迎排砖

lcxlorna

good