拨回成体干细胞生物时钟——可令人体组织返老还童

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科学家回调衰老的成体干细胞生物时钟8 K; y' X6 `" X2 `0 c& w

# L" b% g) [1 z* f, D& s干细胞衰老假说认为成体干细胞与生物体一同衰老，那么，弄清楚影响干细胞自我更新、分裂和分化的机理就可以使衰老的组织再度年轻，并最终治疗许多退行性疾病；8 B$ X3 U" e7 c  G

' W3 J9 l+ ?: j3 i; n  H加州大学研究人员指出通过非编码RNA介入，抑制相关还原转座子毒性转录的积累，可以逆转成体干细胞的衰老过程；+ C3 F* L( y: d- @# G+ N& H) u
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进一步，通过回调细胞时钟的方式，不仅可以逆转老化的人体干细胞，令人称奇的是，通过上调一种“多能性因子”还可以将这些细胞“重置”为更早的发育阶段，, h! M1 P; Y; B% {( y3 `
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/ `7 A. Q+ z( i, RScientists Turn Back the Clock On Adult Stem Cells Aging( z0 G, J% I6 ^+ m' N% R6 K
ScienceDaily (Sep. 21, 2011) — Researchers have shown they can reverse the aging process for human adult stem cells, which are responsible for helping old or damaged tissues regenerate. The findings could lead to medical treatments that may repair a host of ailments that occur because of tissue damage as people age.6 `* b) L- ~; c1 Y6 H! Z; A
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A research group led by the Buck Institute for Research on Aging and the Georgia Institute of Technology conducted the study in cell culture, which appears in the September 1, 2011 edition of the journal Cell Cycle.1 X3 F; ]2 P7 g
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The regenerative power of tissues and organs declines as we age. The modern day stem cell hypothesis of aging suggests that living organisms are as old as are its tissue specific or adult stem cells. Therefore, an understanding of the molecules and processes that enable human adult stem cells to initiate self-renewal and to divide, proliferate and then differentiate in order to rejuvenate damaged tissue might be the key to regenerative medicine and an eventual cure for many age-related diseases. A research group led by the Buck Institute for Research on Aging in collaboration with the Georgia Institute of Technology, conducted the study that pinpoints what is going wrong with the biological clock underlying the limited division of human adult stem cells as they age.  u# Y, B* z+ ]: }

& l3 r6 q6 Z- _2 e/ p8 @"We demonstrated that we were able to reverse the process of aging for human adult stem cells by intervening with the activity of non-protein coding RNAs originated from genomic regions once dismissed as non-functional 'genomic junk'," said Victoria Lunyak, associate professor at the Buck Institute for Research on Aging.# N# e+ m- }7 `2 z5 X* g
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Adult stem cells are important because they help keep human tissues healthy by replacing cells that have gotten old or damaged. They're also multipotent, which means that an adult stem cell can grow and replace any number of body cells in the tissue or organ they belong to. However, just as the cells in the liver, or any other organ, can get damaged over time, adult stem cells undergo age-related damage. And when this happens, the body can't replace damaged tissue as well as it once could, leading to a host of diseases and conditions. But if scientists can find a way to keep these adult stem cells young, they could possibly use these cells to repair damaged heart tissue after a heart attack; heal wounds; correct metabolic syndromes; produce insulin for patients with type 1 diabetes; cure arthritis and osteoporosis and regenerate bone./ [+ K6 f: }$ D6 K  H

# b; I( ?% P) H: uThe team began by hypothesizing that DNA damage in the genome of adult stem cells would look very different from age-related damage occurring in regular body cells. They thought so because body cells are known to experience a shortening of the caps found at the ends of chromosomes, known as telomeres. But adult stem cells are known to maintain their telomeres. Much of the damage in aging is widely thought to be a result of losing telomeres. So there must be different mechanisms at play that are key to explaining how aging occurs in these adult stem cells, they thought.
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Researchers used adult stem cells from humans and combined experimental techniques with computational approaches to study the changes in the genome associated with aging. They compared freshly isolated human adult stem cells from young individuals, which can self-renew, to cells from the same individuals that were subjected to prolonged passaging in culture. This accelerated model of adult stem cell aging exhausts the regenerative capacity of the adult stem cells. Researchers looked at the changes in genomic sites that accumulate DNA damage in both groups.
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# }6 E& a+ V7 y& K2 N6 ]"We found the majority of DNA damage and associated chromatin changes that occurred with adult stem cell aging were due to parts of the genome known as retrotransposons," said King Jordan, associate professor in the School of Biology at Georgia Tech.7 e, Q' I8 ?. f2 Y* o/ |5 T7 {0 f8 m
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"Retroransposons were previously thought to be non-functional and were even labeled as 'junk DNA', but accumulating evidence indicates these elements play an important role in genome regulation," he added.
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While the young adult stem cells were able to suppress transcriptional activity of these genomic elements and deal with the damage to the DNA, older adult stem cells were not able to scavenge this transcription. New discovery suggests that this event is deleterious for the regenerative ability of stem cells and triggers a process known as cellular senescence.
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1 v* k: A6 _2 z" M% s"By suppressing the accumulation of toxic transcripts from retrotransposons, we were able to reverse the process of human adult stem cell aging in culture," said Lunyak.
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  b8 T  K1 x* c$ H/ c$ I7 j"Furthermore, by rewinding the cellular clock in this way, we were not only able to rejuvenate 'aged' human stem cells, but to our surprise we were able to reset them to an earlier developmental stage, by up-regulating the "pluripotency factors" -- the proteins that are critically involved in the self-renewal of undifferentiated embryonic stem cells." she said.
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Next the team plans to use further analysis to validate the extent to which the rejuvenated stem cells may be suitable for clinical tissue regenerative applications.; W! Z6 v& O+ ]3 S8 y
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The study was conducted by a team with members from the Buck Institute for Research on Aging, the Georgia Institute of Technology, the University of California, San Diego, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, International Computer Science Institute, Applied Biosystems and Tel-Aviv University.0 A" t& t0 J4 Q7 |

4 c8 E; N3 x: `! I; rRecommend this story on Facebook, Twitter, 1 |, D+ C! ~, C7 \+ q* j
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) P% T- t3 |5 g+ Fhttp://www.sciencedaily.com/releases/2011/09/110920163215.htm

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* l; ^8 G6 y9 }+ f! vResearchers have shown they can reverse the aging process for human adult stem cells, which are responsible for helping old or damaged tissues regenerate. The findings could lead to medical treatments that may repair a host of ailments that occur because of tissue damage as people age. (Credit: © Tyler Olson / Fotolia)
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7 N7 q7 a1 P7 P, [1 F7 }. {$ Y回复 sunsong7 的帖子
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5 a/ X& S5 _5 D9 \: N1 ]正常体细细衰老是因为端粒缩短，而成体干细胞因能自我更新所以其衰老机制不同于体细胞。研究人员发现，成体干细胞衰老是因为基因组上曾经被认为是非功能性的垃圾DNA序列逆转座子引起的。衰老时，细胞抑制逆转座子转录能力下降，逆转座子转录物引起的有害序列变化积累，最终导致成体干细胞衰老。通过介入该逆转座子非编码性RNA转录物，可以逆转成体干细胞衰老，如果再上调一种多功能因子，还可以转化为更早期的干细胞。% R( n4 k6 s! J( I

) q+ q! a' H( c4 n& s1 n, `Inhibition of activated pericentromeric SINE/Alu repeat transcription in senescent human adult stem cells reinstates self-renewal
0 b: X/ E: ^- I4 i+ ECell Cycle, Volume 10, Issue 17   September 1, 2011
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  e7 Y0 f0 I1 ^; L% H) W3 Whttp://www.landesbioscience.com/journals/cc/article/17543/

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$ K1 R2 X% h" U) s原来是因为衰老过程时，成体干细胞积累起有害的DNA序列变化，最终导致细胞衰老。. ^1 w5 o. F" x' o6 I1 s# W

( ^! o# N' G* D' L3 X6 {  X- U3 Z研究人员发现，在自我更新的成体干细胞中，65%自然发生的可修复的DNA损伤是在转座元件中发生的。一旦在体外衰老时，Alu逆转座子上调转录，导致与永久性DNA损伤位点形成和染色质臂间有效DNA修复缺失相关的细胞核毒性。发生的原因是由于成体干细胞不能招募凝缩蛋白I(condensin I)和黏连蛋白复合体(cohesin complex)。研究结果也证实，Alu重复序列的细胞毒性与人成体干细胞衰老是功能上相关联的。稳定地抑制Alu转录能够逆转细胞衰老，重新恢复这些细胞的自我更新的性质，通过上调所谓的主要多能性调节物还可增加它们的可塑性。

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' i  v! c* r4 e3 D+ z& b& X& }5 T有意思，逆转座子Alu也是DNA重复序列，在DNA中数量还是不少的。所以其影响还是可观的。

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) w4 k- K0 |6 Q: @& D( Y7 u原文参见该帖子：http://www.stemcell8.cn/thread-46776-1-1.html

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, S/ [2 e5 H5 m- E原文参见该帖子：http://www.stemcell8.cn/thread-46776-1-1.html

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