Mol cell：干细胞的自杀开关——Stem Cell Suicide Switch

zorro

Mol cell：干细胞的自杀开关
+ \$ e' C% k2 K" w3 H       人类胚胎干细胞（hESCs）为“牺牲小我，成全大局”这一箴言赋予了全新的意义。不同于所有其他已知的人类细胞类型，hESCs总是准备着一旦发生DNA损伤时便立即拔剑自刎。来自北卡罗来纳大学教堂山分校的研究人员将这一发现发布在了5月3日的《分子细胞》（Molecular Cell）杂志上。
4 \1 y, m8 s- @& [6 r8 O/ m作者们认为，人类胚胎干细胞可形成早期胚胎，并最终生成机体内的每一种细胞类型。因此，DNA损伤触发的快速自毁机制有可能防止潜在的危险突变扩散至整个发育的生物体。 % S$ l; V/ W* E# q- W7 Z: A
      德克萨斯大学圣安东尼奥分校的干细胞研究人员Christopher Navara（未参与该研究）表示：“数据是令人信服的。人类胚胎干细胞采取了一些独特的细胞周期和细胞死亡调控机制来平衡快速增殖，维持稳定、健康的基因组。”
) o5 b. s5 O0 x. \& ]      四年前，北卡罗来纳大学教堂山分校的Mohanish Deshmukh和同事们发现神经元（不同于干细胞，不会发生细胞分裂）可以限制细胞凋亡，使自身度过压力或细胞损伤时期存活下来。为了探究发育谱另一端的凋亡，研究人员进一步分析了不断分裂的人类胚胎干细胞。
( M8 c4 Q# x; ~+ p' o4 l      研究人员提出了两种假说：第一个假说认为人类胚胎干细胞高度抗凋亡是因为这些细胞在胚胎早期只占50%，因此每个细胞都极其宝贵；另一个假说则提出由于每个细胞中的DNA损伤会迅速蔓延至整个胚胎因此人类胚胎干细胞对凋亡高度敏感。“我们觉得它有可能选择了其中的一条路，我们对此感到很好奇，”Deshmukh说。
4 x  Z* s7 D1 M& p0 f; n5 F3 d4 `      首先，研究人员将胚胎干细胞置于可引起DNA损伤的化疗药物中。他们发现相比于成纤维细胞在24小时候才发生死亡，100%的胚胎干细胞仅在短短5小时内便全部死亡。“这与我们和其他研究团体观察到的与人类胚胎干细胞DNA损伤敏感性相关的发现相一致，”Navara说。    M% R5 L- {+ D  G. o
      当Deshmukh研究小组通过另一途径，例如破坏细胞骨架来对胚胎干细胞施压时，发现细胞并没有快速死亡，表明它们只是对DNA损伤急剧敏感。Deshmukh说：“DNA损伤是一种胚胎干细胞无法容忍的创伤。这对于它们而言是灾难性的。它们发生任何的突变都会通过系统迅速地扩散。”% Q. [/ l- x0 b6 S* Y2 K! d
      细胞凋亡是一个漫长的过程，涉及一种称为Bax蛋白的激活，Bax移动到线粒体触发释放caspases，或“刽子手”蛋白引起细胞死亡。为了解析人类胚胎干细胞开始启动这一过程的机制，研究人员用一种抗体标记了Bax，当蛋白质处于活性状态时抗体会发光。他们惊讶地发现在健康人类胚胎干细胞中Bax就已经处于活性状态，这完全不同于其他细胞类型只有在细胞损伤或死亡时Bax才会被激活。Deshmukh说：“我感到震惊，我觉得一定是哪里出现了问题。我们花了大量的时间来说服自己这些细胞是健康的，并没有处于濒死状态。”
5 _; ?7 \4 {$ H  X9 j2 K      研究人员还观察到活性的Bax并没有定位在线粒体而是在高尔基体中。有可能是细胞将活性Bax困住在那里，就如同将枪锁在箱中，防止它意外触发细胞死亡。“细胞激活它，将它栓在一个不会引起即刻损伤的地方。以这种方式，Bax随时准备一接受到命令便即刻行动，”Deshmukh说。
% n1 X) q# Q& _  V% i      有趣的是，人类胚胎干细胞一旦开始分化，即便仅在24小时后，它们也不会再含有活性的Bax，这表明对DNA损伤的极度敏感只存在于早期发育的短短数天内。 3 C' H; }3 h- j2 |! `  ^0 P/ @
      现在研究小组正在开展研究是什么使得Bax在人类胚胎干细胞中组成性激活，它是如何定位到高尔基体的。尽管hESCs被广泛应用到再生医学研究中，科研人员对于它们的生物学仍然知之甚少。Deshmukh说：“大多数研究都聚焦于这些细胞形成分化细胞的机制。我们很惊讶，我们对于基础生物学了解的实在是太少了。”
/ Q1 z* B2 `, ?6 g; g0 ]/ O
8 h$ R( }$ V8 Y4 W/ g9 {8 i: h: h4 M

Stem Cell Suicide Switch  V& s# H; T. Z5 h0 k% g
Human embryonic stem cells swiftly kill themselves in response to DNA damage.By Megan Scudellari | May 3, 2012 % I6 f4 a" T5 s: g* F6 K

$ a4 a2 e" o+ n9 d7 s2 jHuman embryonic stem cells (hESCs) form the early embryo and eventually give rise to every cell type in the body. Because of this, a rapid self-destruct mechanism activated by DNA damage may prevent potentially dangerous mutations from spreading through the developing organism, the authors concluded.
) i+ p: }8 G+ h, C: B- L# C& q1 W+ R9 u+ |: P
The data is “convincing,” wrote Christopher Navara, who studies stem cells at the University of Texas at San Antonio and was not involved in the research, in an email to The Scientist. “hES cells have adopted a number of unique cell cycle and cell death regulatory mechanisms” to balance their rapid proliferation with maintaining a stable, healthy genome, he wrote.
3 Y9 f. f+ \/ U( u* F- H2 _% |& g( x7 R& N
Four years ago, Mohanish Deshmukh and colleagues at the University of North Carolina at Chapel Hill found that neurons—which, unlike stem cells, do not divide—restrict apoptosis, or cell death, allowing them to survive through periods of stress or cell damage that might otherwise stimulate apoptosis. To explore apoptosis at the other end of the development spectrum, the researchers next analyzed human ESCs, which constantly divide.
$ d  k0 r( X% B' W0 Z, F! h
  n, C& u0 I) WThey had two hypotheses: the hESCs would be highly resistant to apoptosis since there are only about 50 of them in the early embryo and thus each is valuable; or they would be highly sensitive to apoptosis since DNA damage in even a single cell would quickly spread through an embryo. “We figured it could go either way,” said Deshmukh. “We were very curious.”: Z' K9 j3 ~1 W- B$ \

" }) t/ U, ~1 v! r2 x! H' M4 m( oFirst, the team doused hESCs in a chemotherapy drug that causes DNA damage. Almost 100 percent of the hESCs died in just 5 hours, compared to 24 hours for fibroblasts. The finding is “consistent with what we and others have observed regarding sensitivity to DNA damage in hES cells,” said Navara.
) }: K) V: L* _% c& e" ~; c7 g6 R0 {' I; I
When Deshmukh’s team stressed the ESCs in other ways, such as damaging the cytoskeleton, the cells did not die as quickly, demonstrating their acute sensitivity to DNA damage. “DNA damage is the one insult these embryonic stem calls can’t tolerate,” said Deshmukh. “It’s catastrophic for them. Any mutations they occur will be propagated rapidly through the system.”! g% D' t9 h. X6 n- x7 G0 P9 P
. }' l3 [& j: m1 ^; ?0 F2 a
Apoptosis is traditionally a lengthy process that involves the activation of a protein called Bax, which travels to the mitochondria and initiates the release of caspases, or “executioner” proteins that cause cell death. To investigate how hESCs initiate the process so rapidly, the researchers tagged Bax with an antibody that lights up when the protein is active. They were surprised to find that Bax is already active in healthy hESCs, unlike every other cell type in which Bax is activated only when a cell is damaged or dying. “I was stunned,” said Deshmukh. “I thought something was wrong. We spent a lot of time convincing ourselves that these cells were healthy and not actively dying.”
* R$ z+ w" ^8 `7 G5 J6 M$ T- n2 I4 H+ @! X& g3 R
The team also saw that active Bax was not located in the mitochondria but in the Golgi, a packaging organelle. It is possible that cells sequester active Bax there, like a gun locked in a case, to prevent it from accidentally triggering cell death. “The cells’ activated it and tethered it to a place where it is not causing immediate damage,” said Deshmukh. That way, Bax is ready to go at a moment’s notice.
( ?. `# U; n3 c- C0 R% z% H2 [  C. n) n/ u8 `7 s
Interestingly, as soon as hESCs began differentiating, even after just 24 hours, the cells no longer contained active Bax, suggesting that extreme sensitivity to DNA damage lasts only for a few days during early development.
. a, g1 ~- J" L' d7 z0 d, ?8 S, f/ o& n
The team is now investigating what makes Bax constitutively active in hESCs and how it is localized to the Golgi. Though hESCs are popular in regenerative medicine research, researchers still know little about their biology, said Deshmukh. “Most research focuses on how these cells become differentiated cells,” he said. “I’m amazed that we don’t understand much about their basic biology.”: r# `9 S  R3 I+ T) r. Q4 s, \" @

; E1 {+ H' c% l9 k8 s/ S) _R. Dumitru, et al. “Human embryonic stem cells have constitutively active Bax at the Golgi and are primed to undergo rapid apoptosis,” Mol Cell, doi:10.1016/j.molcel.2012.04.002, 2012.  ~% j. R& q5 g1 V) y$ y3 W7 g: A
5 u4 I$ u6 T! N0 k6 D
  

一枝独秀

是不是通过内质网应激产生凋亡而保护自身啊，这应该是干细胞自我保护的机制之一，应该还有自噬的参与吧？

卿尘

~~~~