7 |% _) k3 M s5 a% W, A成果之三：这项研究也产生一个主要的疑问，即是多功能干细胞分化过程改变代谢模式，还是代谢模式的变化改变分化过程，也就是所谓鸡或蛋的问题。! e9 c E3 ^$ b) @
. a5 u; k. g# O k. }
为此，在这些干细胞中，研究人员过表达UCP2，结果显示在多能性标记物或细胞成熟发生变化之前，代谢模式就已改变，这说明至少就UCP2而言，代谢变化影响分化，而不是另外相反情形。这对于证明代谢变化是驱动细胞分化过程的原因是比较重要的。但是，这仍然未解决如何精确操作细胞代谢来控制细胞分化这个关键问题，研究人员正试图解决这个问题。 F- E6 v6 B7 q5 w
, ~* h+ V- w- N/ Q, `1 q( U" r 研究意义： * \- `5 I% U3 b意义之一：就UCP2而言，代谢变化影响细胞分化，那么人们就可以通过操纵UCP2来改变干细胞分化的方向，而且这一点不仅是对人胚胎干细胞如此，对于人诱导性多功能干细胞也是如此。 9 v3 ]' w1 W% I6 k8 |6 f$ _( N5 Z意义之二：因为多功能干细胞和癌细胞代谢似乎非常相似，人们有可能利用这一发现治疗表达UCP2的恶性肿瘤。沉默UCP2有可能强迫癌细胞呼吸，从而有可能破坏它们快速生长的能力。 ; ], E1 V$ }1 S+ g( c- v& I意义之三：鉴于在已分化的细胞中表达UCP2阻碍它们的成熟，这就要求人们在进行研究时应该考虑这一点，不可忽视。 ! e$ t! j; I% P2 R/ [- {$ [- F意义之四：运转正常的代谢对于产生安全和高质量细胞是非常重要的。% V% l. n! X; ~# G# ^
( T' q1 D: f l 不足之处：6 u6 s9 _7 b* b5 x1 b" l) r- j naturalkillerce个人意见：虽然指明了人多功能干细胞的代谢变化与它的分化过程密切相关，而且就UCP2而言，干细胞的代谢变化影响它的分化过程，而不是相反情形。但是这仍然未解决如何精确操作细胞代谢来控制细胞分化这个关键问题。因为代谢是许多途径组成的网络，要精确操作细胞代谢来控制细胞分化，不单是通过一个UCP2就能解决的，还需要人们采取更多措施去深刻了解干细胞代谢和分化的机制，从而为干细胞最终大规模进入临床应用打下坚实基础。 / P$ m" @& Q! a# y1 {+ V, N2 M8 X) f6 f A/ I 原文信息：' d6 g* ]/ N% T* R
UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells- [6 a( E9 C" E( S8 ?3 `) J
* ]* {3 B. B" L# C. g0 l! B
Jin Zhang, Ivan Khvorostov, Jason S Hong, Yavuz Oktay, Laurent Vergnes, Esther Nuebel, Paulin N Wahjudi, Kiyoko Setoguchi, Geng Wang, Anna Do, Hea-Jin Jung, J Michael McCaffery, Irwin J Kurland, Karen Reue, Wai-Nang P Lee, Carla M Koehler, Michael A Teitell. 2 S/ T( T/ u: u) A 8 u! e6 T) B/ y3 L6 P) O& j' \The EMBO Journal, 2011; DOI: 10.1038/emboj.2011.401 - A9 b' }9 y ~" E" ? http://www.nature.com/emboj/jour ... /emboj2011401a.html % d9 ~5 H$ a6 W- U作者: naturalkillerce 时间: 2011-11-18 00:38
回复 naturalkillerce 的帖子; A. l1 {1 \1 q2 b' M/ S5 D
- h6 t. a: r3 N: J" Y+ i4 y0 g% o Stem Cell Researchers Uncover Mechanism That Regulates Human Pluripotent Stem Cell Metabolism 2 ^" |& G% A/ `$ G. j; W* t1 B/ \9 L( e& I2 u
ScienceDaily (Nov. 15, 2011) — Human pluripotent stem cells, which can develop into any cell type in the body, rely heavily on glycolysis, or sugar fermentation, to drive their metabolic activities. 7 f, a2 b" ]$ \3 f / I( Y/ Q/ y' Y( i; _5 R2 GIn contrast, mature cells in children and adults depend more on cell mitochondria to convert sugar and oxygen into carbon dioxide and water during a high energy-producing process called oxidative phosphorylation for their metabolic needs. " Y% q7 s3 d' ]2 r/ r8 @ V 4 m' u- I: M7 l, j! k: s% m: EHow cells progress from one form of energy production to another during development is unknown, although a finding by UCLA stem cell researchers provides new insight for this transition that may have implications for using these cells for therapies in the clinic. - m. Z! m" q* r 9 X9 S+ a, O7 D! _, e k ?1 `: O% KBased mostly on visual appearance, it had been assumed that pluripotent stem cells contained undeveloped and inactive mitochondria, which are the energy-producing power plants that drive most cell functions. It was thought that stem cell mitochondria could not respire, or convert sugar and oxygen into carbon dioxide and water with the production of energy. This led most scientists to expect that mitochondria matured and gained the ability to respire during the transition from pluripotent stem cells into differentiated body cells over time.5 V/ \2 @" B) k# c
! v1 c3 o2 W% e4 L
Surprisingly, UCLA stem cell researchers discovered that pluripotent stem cell mitochondria respire at roughly the same level as differentiated body cells, although they produced very little energy, thereby uncoupling the consumption of sugar and oxygen from energy generation. Rather than finding that mitochondria matured with cell differentiation, as was anticipated, the researchers uncovered a mechanism by which the stem cells converted from glucose fermentation to oxygen-dependent respiration to achieve full differentiation potential.$ \7 R# F+ x# y7 H0 @: O
9 i# Q1 v% |4 ^# B/ XThe four-year study appears in the Nov. 15, 2011 issue of The EMBO Journal, a peer-reviewed journal of the European Molecular Biology Organization. Teitell collaborated with Carla Koehler, a UCLA professor of chemistry and biochemistry, for the study.( g r. K4 n0 R0 y
/ T2 H! ~! h5 B! ?, i"A lot of attention is being paid to the role of metabolism in pluripotent stem cells for making properly differentiated cell lineages for research and potential clinical uses," said study senior author Dr. Michael Teitell, a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and a professor of pediatrics, pathology and laboratory medicine, and bioengineering. $ Q B/ v& i1 u " V) }, Q. _3 x( kThe initial question prompting our study was whether metabolism in pluripotent stem cells and cancer cells, which also rely heavily on glycolysis, were molecularly similar," he said. "This question led us to study the details of energy-generation by mitochondria in pluripotent stem cells." & p3 Y- `1 b; M& R2 u$ l g/ m" w5 r2 {* Q. E
Cells make energy in the form of ATP mainly in two ways, by glucose uptake and fermentation in the cytoplasm or by using respiration, in which glucose and oxygen are consumed to make carbon dioxide and water to fuel cell functions. Teitell and his team expected that pluripotent stem cells could not respire because of prior reports on the immature appearance and paucity of mitochondria. ' ]( \: ~ ]) q' l6 V1 k5 l. s% M( Q. c& l( |* E& T
Teitell's team found that the molecular complexes responsible for respiration, called the electron transport chain, in the mitochondria of pluripotent stem cells were functional, and yet the cells instead relied on glycolysis for energy production. The researchers speculated that there were one or more unknown regulators that kept the stem cells from respiring, since the electron transport chain was functional.- z/ c* i& i4 T
# _1 F' W3 R0 h, @# M& u/ }
Jin Zhang, a graduate student and first author of the study, discovered that a protein called uncoupling protein 2 (UCP2), was highly expressed in the stem cells. He also found that UCP2 blocked respiration substrates derived from sugar from gaining access to the mitochondria, instead shunting them to the glycolytic and biosynthesis pathways located in the cytoplasm, inhibiting the stem cell's ability to respire as a method for generating energy.1 C; P9 D" u# Z( Q" j* E7 E0 f% V
/ i4 K1 y; b' M" ~% p* t
As pluripotent stem cells were driven to develop into mature cell types, UCP2 expression was shut off, allowing respiration substrates to enter the mitochondria for energy generation, switching the cells from glycolysis to oxidative phosphorylation. Manipulating UCP2 expression, by keeping it switched on in differentiating cells, disturbed their maturation, a finding that could make them unsuitable for clinical use and also pointing to the importance of properly functioning metabolism for generating safe, high quality cells., v" n( @6 m0 I+ r; T; E
' N |- y' D; D7 Z+ x
Teitell and his team confirmed these findings in both human embryonic stem cells and in induced pluripotent stem cells, which are mature body cells that are genetically reprogrammed to have similar abilities and attributes as the pluripotent embryonic stem cells. - T$ [$ c/ o, q6 w 8 T* k! A8 w; i3 `! F$ h; g"A main question that evolved during the study was whether it was the process of pluripotent stem cell differentiation that was altering the pattern of metabolism, or was it the change in the pattern of metabolism that altered the process of differentiation, a typical chicken-or-the-egg question," Teitell said. "We over-expressed UCP2 in the stem cells and showed that metabolism patterns changed before markers of pluripotency or cell maturation changed, indicating that changes in metabolism affect changes in differentiation and not the other way around, at least for UCP2. This was important, to show causation for metabolic changes in driving the process of cell differentiation. However, it still leaves open the key question of exactly how manipulating cell metabolism controls cell differentiation, a question we are working hard to address.", @- ]6 N" Q N
1 G4 T9 ? g. z6 v
Since metabolism in pluripotent stem cells and cancer cells appear quite similar, Teitell said the finding could potentially be used to target UCP2 in malignant tumors that express it, of which there are many. Silencing UCP2 could force cancer cells to respire, which might impair their ability to grow quickly.8 T7 s) ?) B, o; V# ?! A: S. N \
0 x& V3 S- j4 z4 t; j
The study was supported in part by the California Institute for Regenerative Medicine, an Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research training grant, the National Institutes of Health and the National Center for Research Resources. 4 w% G; p( V9 q" N3 d# I/ Y* B/ P' S http://www.sciencedaily.com/releases/2011/11/111115103503.htm作者: eileenyangliu 时间: 2011-11-18 09:39
再次验证基础知识怎么强调都不过分（科学院吴乃虎教基因工程时反复强调），% ]0 H, Q& |5 d' S! t. m5 O
不知道还有多少朋友记得生物化学教材里的细胞糖代谢的2条途径， 三羧酸循环和糖酵解（糖酵解该名称应该是地道的中文翻译，而不是发酵）作者: naturalkillerce 时间: 2011-11-18 17:28
回复 fguw 的帖子5 x5 V" S5 G2 w. L9 Q+ p
+ M/ O3 Q3 A' p. A/ S S& n
呵呵，这你就错了。糖酵解本身就含有发酵的意思，当然跟国人想象中的发酵意思有些差别。 3 P; H; W$ y. Y: E原文不也说，glycolysis就等于 sugar fermentation。作者: iamxuchen 时间: 2011-11-18 23:43