干细胞之家 - 中国干细胞行业门户第一站

标题: 中国学者Stem Cell获干细胞新发现 [打印本页]

作者: 细胞海洋 时间: 2011-11-4 15:47 标题: 中国学者Stem Cell获干细胞新发现

来自香港中文大学的研究人员发现将干细胞重组为更基础的形式，可以增加移植的有效性，这篇改善移植干细胞的存活率与有效性的最新研究公布在Stem Cells杂志上。 ( J+ Y' }  V8 p5 q

这项研究由香港中文大学陈小章（Hsiao Chang Chan）教授领导完成。陈小章教授是上皮细胞相关的跨学科研究领域的权威科学家，2007年荣获长江学者成就奖。
由于干细胞研究人员从人体的一部分获取细胞并对它们进行遗传学改造，以便其发挥专门功能，对分化的研究带来了多种突破进展。但是，如果植入细胞与目标区域的细胞太过相似，那么它们可能不具备修复受伤组织的可塑性。 ' m8 {$ U! O8 r. e& b7 ^7 \9 w
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“干细胞分化与移植已被证明能够改善包括退化性疾病和血液供给障碍在内的疾病的功能”，陈博士说道。“但是，患者体内的移植细胞的存活率限制了它们的整体效力，这对于临床应用来说是一个障碍。”
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为了克服这一问题，陈博士的研究团队对去分化进行了研究，这是一个能够将专门的分化细胞重新转为更原始的细胞的过程。 + u) M, e8 J7 k  h9 P' _

该团队将他们的研究重点放在了骨髓间充质干细胞（MSCs），这种细胞可以通过分化过程转化为多种细胞类型。骨髓多能干细胞具备分化成形成骨骼（骨细胞）、软骨（软骨细胞）和脂肪组织（脂肪细胞）的三种基本细胞系的潜力。 ' N& B+ ~: ?' g3 ~

该团队首先将骨髓多能干细胞分化成神经元细胞系，然后去掉分化条件，使细胞重新转化为具有更基础的细胞特征的形式。 ) X, V- ~5 n! J

在这一过程之后，该团队记录了移植后的细胞存活率获得提升。在一个动物模型中，研究人员发现，相比于活体标本和实验室实验中未经过操作的干细胞，去分化细胞在改进认知功能以及促进中风恢复方面更为有效。 8 r  ]; W$ I5 @0 M7 K, L  |* v# K$ I; o

结果证实，去分化是一种可行的技术，可用来将细胞重塑为更早期、更原始的状态，使它们重组后具有更高的细胞存活率，从而提高它们的临床应用潜力。

“多能干细胞经过重组后在对患者具有应用潜力的动物模型中可以获得更高的存活率和治疗效果，这一发现非常激动人心，因为它可以为克服基于细胞的疗法中的较低细胞存活率提供一种新型的临床可行的方法”，陈博士总结道。“目前我们正在研究重组多能干细胞用于其他治疗应用的其他有利性能。”

“许多研究人员推测，分化应能够改进干细胞的移植功效，但是将细胞分化到何种程度可以获得最佳的效果仍是一个很困难的问题。陈博士的研究团队帮助给出了答案，他们在对细胞进行去分化之前，通过将其预分化为所需的细胞系，对间叶干细胞进行处理，使得多能干细胞更容易操作和移植”，《STEM CELLS》副主编Mark Pittenger博士说道。- b" b8 X( @* m) N; |
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“对于未来的研究工作而言，仍然有不少有趣的问题，比如哪些因子在维持去分化状态的预分化干细胞中得到表达，能否将去分化细胞冷冻以供将来使用？”8 A+ a5 S* [* b- K8 O

(http://www.ebiotrade.com/)

作者: cgc123 时间: 2011-11-4 16:43

学习了，哈哈！做干细胞最头疼的就是细胞多次传代以后细胞就老化或则分化了，这样失去了良好的增殖和分化能力。虽然加bfgf等生长因子能够一定程度上保持干细胞的增殖能力，但也不是很理想。这个的研究成果不知道能不能应用到保持干细胞持久的增殖和分化能力上？

作者: bigsnow55 时间: 2011-11-4 17:57

能否提供原文链接，谢谢！

作者: naturalkillerce 时间: 2011-11-4 22:01

回复 bigsnow55 的帖子

Dedifferentiation-Reprogrammed Mesenchymal Stem Cells with Improved Therapeutic Potential
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Stem cell transplantation has been shown to improve functional outcome in degenerative and ischemic disorders. However, low in vivo survival and differentiation potential of the transplanted cells limits their overall effectiveness and thus clinical usage. Here we show that, after in vitro induction of neuronal differentiation and dedifferentiation, upon withdrawal of extrinsic factors, mesenchymal stem cells (MSCs) derived from bone marrow, which have already committed to neuronal lineage, revert to a primitive cell population (dedifferentiated MSCs) retaining stem cell characteristics but exhibiting a reprogrammed phenotype distinct from their original counterparts. Of therapeutic interest, the dedifferentiated MSCs exhibited enhanced cell survival and higher efficacy in neuronal differentiation compared to unmanipulated MSCs both in vitro and in vivo, with significantly improved cognition function in a neonatal hypoxic-ischemic brain damage (HIBD) rat model. Increased expression of bcl-2 family proteins and microRNA-34a appears to be the important mechanism giving rise to this previously undefined stem cell population that may provide a novel treatment strategy with improved therapeutic efficacy.
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DOI: 10.1002/stem.764

http://onlinelibrary.wiley.com/doi/10.1002/stem.764/abstract

作者: yxc 时间: 2011-11-4 22:34

摘自www.InvestorStemCell.com 的报道：
Posted by iCELL News, on 04th November 2011, in Featured.& V+ C3 c4 c/ M; N; _6 g9 p0 B
www.investorstemcell.com

Prompting expanded mesenchymal stem cells (MSCs) to undergo neuronal differentiation and then triggering them to dedifferentiate back to a more stem-like state results in a population of cells that exhibits enhanced survival when transplanted in vivo, and a greater ability to redifferentiate back into neuronal cells, investigators claim.

A team led by researchers at the Chinese University of Hong Kong was interested to see whether MSC-derived neuronal progenitor cells that were dedifferentiated (de-MSCs) would have different properties to the MSCs from which they were originally derived. Their findings showed that the de-MSCs displayed multipotent gene expression profiles similar to those of their unmanipulated MSC counterparts, but also upregulated the expression of genes required for neuronal differentiation and survival.

When MSCs and de-MSCs were then transplanted into a rat model of brain damage, the de-MSCs demonstrated a significant survival advantage, and led to comparatively greater levels of functional improvement in treated animals. The University’s Hsiao Chang Chan, Ph.D., and colleagues, suggest their findings could translate into more effective stem-cell based regenerative therapies. “It may provide a novel and clinical practical method to overcome low cell survival in cell-based therapy,” Dr. Chan states. “We are currently exploring other beneficial properties of the reprogrammed MSCs for other therapeutic applications.”

The team reports its findings in Stem Cell in a paper titled “Dedifferentiation-reprogrammed mesenchymal stem cells with improved therapeutic potential.”
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Research has demonstrated that bone marrow stromal stem cells, also known as mesenchymal stem cells, have the capacity to differentiate into a wide range of cell types outside the mesodermal lineage, including neuron-like cells, the researchers report. Unfortunately, while transplantation studies using MSC-derived cells in animal models of diseases including Parkinson disease, stroke, cerebral ischemia, and spinal cord injury have shown beneficial effects, most have reported low levels of cell survival and neuronal differentiation in vivo.

Dedifferentiation, meanwhile, is a process that re-routes cell fate by reverting differentiated cells into an earlier, more primitive phenotype, with an altered genetic expression pattern that gives the cells a broader differentiation potential. While the process is common in, for example, amphibians that can regenerate complex body structures throughout life, research has only recently provided evidence that mammalian cells can undergo dedifferentiation.' A2 |: }, x  S# Q( y, G

Building on both their own and independent research, the Chinese University team looked more closely at dedifferentiated mammalian MSCs to investigate whether they may exhibit altered therapeutic potential compared with the MSCs from which they were originally derived.& h, V; F' k/ Q0 B* l' @9 @
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The researchers first isolated MSCs from rat bone marrow, expanded the cells and established monoclonal MSC clones. The resulting clones were then triggered to undergo neuronal differentiation. Once neuronal induction was established, the culture medium was changed again and cells were triggered to undergo dedifferentiation, reverting back to a stem cell state. The de-MSCs were passaged every 4–5 days, and induced to undergo neuronal redifferentiation by transferring washed cells to the appropriate modified neuronal medium.
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Neuronal differentiation, dedifferentiation, and redifferentiation of monoclonal MSCs were confirmed by the concomitant upregulation and reversion of multiple neurogenesis marker genes as determined by PCR array, the researchers explain. Virtually 100% of the redifferentiated cells were NF-M and MAP2 positive. Interestingly, they add, while dedifferentiation from the neuronal to the stem cell phenotype was associated with a clear reduction in the expression of neuronal proteins, the expression of these neuronal markers in de-MSCs was higher than that in undifferentiated MSCs.
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This suggested that de-MSCs retained some neuronal traits, and therefore presumably carried higher potential for redifferentiation into neurons. “Indeed, de-MSCs could undergo dedifferentiation with full expression of the neuronal markers,” the authors note. Moreover, the re-neurons derived from de-MSCs were significantly more hyperpolarized than neuronal progenitors derived from MSCs, indicating that they have a higher potential to develop into mature functional neurons.0 w7 t' ]8 @! M( S# I  }2 i

Fluorescence-activated cell sorting (FACS) profiling indicated that de-MSCs retained an immunophenotype similar to that of undifferentiated MSCs, and both cell types could be induced in vitro to acquire typical characteristics of mature osteoblasts, adipocytes, and chondrocytes, indicating that the de-MSCs retain mesodermal potential. Gene expression profiling indicated that compared with MSCs, the de-MSCs demonstrated upregulation of about 1.5% of genes, and twofold or more downregulation of about 3% of genes.

Notably, the authors say that the most highly enriched transcripts in de-MSCs included critical and growth factor genes required for neuronal development or neurogenesis, although genes that were abundantly expressed in MSCs were also expressed at the same level in de-MSCs. And when the authors looked more closely at nestin and musashi-1, two genes that are widely considered as specific markers of neural stem cells and progenitors, they found that while only about 20–30% of undifferentiated MSCs expressed the genes, some 57–63% of de-MSCs were nestin- and musashi-positive cells.

The results thus far indicated that de-MSCs might represent a population of stem cells with increased neuronal potential, and in vitro studies also showed that compared with unmanipulated MSCs, they also demonstrated increased viability under conditions of oxidative stress (effected by treatment with H2O2). In fact, 13 out of 83 apoptosis-related genes were differentially expressed between MSCs and de-MSCs, with further analyses suggesting that the increased survival of de-MSCs under oxidative stress conditions might be due to enhanced expression of bcl-2 family proteins.
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This finding led the team to look specifically at miR-34a expression in both basal and H2O2-treated MSCs and de-MSCs, because prior research has indicated that miR-34a is involved in regulating apoptosis through direct targeting of bcl-2. They found that miR-34a was markedly increased upon H2O2 treatment in MSCs whereas there was no change of miR-34a detected in de-MSCs, indicating that miR34a-targeted bcl-2 inhibition plays a role in the differential survival of MSCs and de-MSCs following H2O2 administration.
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The miRNA investigation also threw up the finding that de-MSCs exhibited higher basal levels of miR-34a than MSCs. Given that previous studies had implicated this miRNA in neuronal differentiation, it was feasible to postulate that miR-34a could be associated with the increased neuronal potential of de-MSCs. In fact, they found that miR-34a expression increased over time as the neuronal differentiation of de-MSCs progressed. Of even more interest, they add, was the observation that miR-34a expression changed in parallel with both the neuronal differentiation and dedifferentiation process, providing a hint that miR-34a could be involved in regulating neurogenesis and contribute to the higher neuronal potential of de-MSCs. Supporting this notion was the finding that ectopic overexpression of miR-34a in MSCs resulted in a significant increase in three neural stem cell marker genes that were already upregulated in the de-MSCs.
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To evaluate the therapeutic potential of de-MSCs, the researchers first exposed primary cultures of hippocampus neurons (PHN) to H2O2, and then co-cultured them with MSCs or de-MSCs. The H2O2 exposure caused the PHNs to undergo cytoskeletal disaggregation and axonal fragmentation. Co-culturing these damaged cells with MSCs or de-MSCs led to marked increases in the number of viable cells, but there were significantly more viable cells evident after co-culturing with de-MSCs than with MSCs.
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Moving on to in vivo tests, the team focused on a rat model of neonatal hypoxic-ischemic brain damage (HIBD), induced in week-old animals by occlusion of unilateral common carotid artery. The HIBD rats were then treated using lateral ventricle injection of either GFP-tagged MSCs or de-MSCs. While both transplanted GFP-MSCs and de-MSCs were readily found near the injection sites at three days after transplantation, GFP expression could only be detected in de-MSC-treated animals by day seven after transplantation. A number of the transplanted cells had also migrated away from the injection site, and some of the GFP-de-MSCs expressed differentiated neuronal markers NF-M or MAP2.
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The researchers then investigated whether the better survival of de-MSCs might be due to a greater ability to promote angiogenesis in the ischemic region. They stained ischemic brain tissue of both MSC- and de-MSC-transplanted rats for the endothelial marker CD31, seven days after treatment. The results confirmed that compared with untreated animals, CD31-positive vessels increased significantly in the stem cell-transplanted groups, but in comparison with MSC recipients, tissue from the de-MSC cohort showed much higher vessel density. “Of note, we observed some GFP-positive cells in de-MSC group were immunoreactive to CD31, indicating transplanted de-MSCs might have been transformed into endothelial cells or formed fusion cells with preexisting endothelial cells,” they state. “These results suggest that de-MSCs may be more pluripotent as compared to undifferentiated MSCs in promoting angiogenesis, which may contribute to their better survival in the ischemic region.”
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This latter possibility was confirmed when the researchers compared the functional recovery of HIBD rats after treatment with MSCs and de-MSCs. The results of shuttle box tests showed that both treated groups significantly improved cognitive function, but as time went on, the functional improvements exhibited by the de-MSC-treated animals became obviously greater than those of the MSC-treated rats, and the tested behaviors were hardly different from those of control rats." o. }& H+ w5 v( q' U, C

“The present study has characterized a previously undescribed dedifferentiation-reprogrammed stem cell population that exhibits enhanced cell survival and differentiation with improved therapeutic potential in vitro and in vivo,” the authors conclude. “With easy culture manipulation and low tendency of tumor formation, as compared to the more complicated genetic manipulation and higher risk of induced pluripotent stem cell forming teratomas upon transformation, de-MSCs may offer at least two advantages over iPS in cell-based therapy…Increased expression of bcl-2 family proteins and microRNA-34a appears to be the important mechanism giving rise to this previously undefined stem cell population that may provide a novel treatment strategy with improved therapeutic efficacy.”

作者: lianzhimin 时间: 2011-11-4 22:49

看了文章的摘要，我并不觉得发现几个去分化的因子和定向分化因子或许可以用于干细胞自我更新维持或定向分化就是这篇文章最值得借鉴的成果。干细胞的培养与增殖已成体系，没什么可说的，文中提到的亦是如此。我觉得这篇文章最卖钱的地方在于他不是直接注射未分化细胞或机体需要的已分化功能体细胞，而是将未分化的细胞分化后去分化，对，就是分化后去分化，这个看似画蛇添足的步骤是这篇文章最亮的地方。为什么要画蛇添足？为什么这样做之后能大大提高治疗效率？私以为是这样子的：未分化细胞诱导分化再去分化，然后将这些二次去分化细胞植入病患处，就像一个人画了一张素描画，然后用橡皮擦掉了，再将这幅被橡皮擦干净的纸给一个小孩子叫他在这张纸上再次画一张一样的素描画，因为第一次画画留下的痕迹轮廓的存在，当然这个小孩子要比那些在崭新白纸上画一幅山水画要容易得多。这篇文章就是很巧的应用了分化过程中不可抹去的基因表达痕迹和未分化细胞的增殖与功能性潜力来提高移植治疗效率的，很是巧妙的心思！未看全文小生妄言，还请各位大侠多多指正！

作者: yxc 时间: 2011-11-5 09:30

全文[attach]35128[/attach]

作者: 573639471 时间: 2011-11-5 11:39

lianzhimin 发表于 2011-11-4 22:49 / g4 E) h5 K1 U
看了文章的摘要，我并不觉得发现几个去分化的因子和定向分化因子或许可以用于干细胞自我更新维持或定向分化 ...

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有趣啊分化后再去分化，这个是不是跟特定的体细胞去分化一个意思啊，直接取目的细胞的体细胞类型去分化就行了，不需要多此一举吧

作者: menghy 时间: 2011-11-6 21:51

和大家讨论下：
文章说的：“去分化是一种可行的技术，可用来将细胞重塑为更早期、更原始的状态，使它们重组后具有更高的细胞存活率，从而提高它们的临床应用潜力。”居然已经分化成了神经细胞系了，那为什么还能保持细胞更早期、更原始的状态呢？

作者: menghy 时间: 2011-11-6 21:53

lianzhimin 发表于 2011-11-4 22:49
: c+ N. P0 ?3 j, m f看了文章的摘要，我并不觉得发现几个去分化的因子和定向分化因子或许可以用于干细胞自我更新维持或定向分化 ...

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部分同意楼上的观点，这表文章的亮点是加一定诱导分化条件让细胞分化，去除分化后，注入体内，这样细胞在体内的影响下会朝相应的方向更容易分化和生长。

作者: bin 时间: 2011-11-6 21:59

回复 lianzhimin 的帖子 U9 V) y. Z6 q# M+ I

我很同意你的看法。但是体内的诱导因素太多，将干细胞直接移植到体内的话可能会分化为不需要甚至对再生起到抑制作用的细胞，虽然说先预分化然后再去分化可以在西部内部留下“印记”，但是谁能说那些去分化的干细胞不会再分化为不需要的细胞呢。这个结果是否真的可以推广到所有干细胞的临床治疗还有待验证。

作者: cell1314 时间: 2011-11-8 10:13

yxc 发表于 2011-11-5 09:30 1 [5 Q! N# \! U0 ]" O1 S
全文

yxc兄，你提供的全文怎么是个error？

作者: yxc 时间: 2011-11-8 13:57

回复 cell1314 的帖子; A7 G# [7 u0 g% h
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我上传前看了没错啊，其他战友看了吗？有问题的话我重发

作者: pailishi 时间: 2011-11-8 15:29

同意6楼的观点，正如文章所述“如果植入细胞与目标区域的细胞太过相似，那么它们可能不具备修复受伤组织的可塑性。”所以是将MSCs诱导分化，而不是直接使用体细胞；另外，“去分化是一种可行的技术，可用来将细胞重塑为更早期、更原始的状态，使它们重组后具有更高的细胞存活率，从而提高它们的临床应用潜力。”因此去分化并不是多此一举，这样提解决了“患者体内的移植细胞的存活率限制了它们的整体效力，这对于临床应用来说是一个障碍。” 分化去分化的最终目的还是分化保留印迹、保持增殖修复功能。

作者: pailishi 时间: 2011-11-8 15:30

同意6楼的观点，正如文章所述“如果植入细胞与目标区域的细胞太过相似，那么它们可能不具备修复受伤组织的可塑性。”所以是将MSCs诱导分化，而不是直接使用体细胞；另外，“去分化是一种可行的技术，可用来将细胞重塑为更早期、更原始的状态，使它们重组后具有更高的细胞存活率，从而提高它们的临床应用潜力。”因此去分化并不是多此一举，这样提解决了“患者体内的移植细胞的存活率限制了它们的整体效力，这对于临床应用来说是一个障碍。” 分化去分化的最终目的还是分化保留印迹、保持增殖修复功能。

作者: pailishi 时间: 2011-11-8 15:31

同意6楼的观点，正如文章所述“如果植入细胞与目标区域的细胞太过相似，那么它们可能不具备修复受伤组织的可塑性。”所以是将MSCs诱导分化，而不是直接使用体细胞；另外，“去分化是一种可行的技术，可用来将细胞重塑为更早期、更原始的状态，使它们重组后具有更高的细胞存活率，从而提高它们的临床应用潜力。”因此去分化并不是多此一举，这样提解决了“患者体内的移植细胞的存活率限制了它们的整体效力，这对于临床应用来说是一个障碍。” 分化去分化的最终目的还是分化保留印迹、保持增殖修复功能。

作者: pailishi 时间: 2011-11-8 15:37

同意6 楼的观点，分化和去分化的最终目的就是希望保留分化的印迹和干细胞的增殖潜能，解决移植存活率低的问题。

作者: nines 时间: 2011-11-8 19:35

个人比较倾向于喜欢这篇文章，就像楼上说的那样，这篇文章最大的亮点就是干细胞分化后的去分化，这一点很新颖。从提高细胞植入后的成活率出发，想办法提高它的生存力，想到了让其去分化的方法，这篇文章里包含的解决问题的科研思路也很值得学习！

作者: iamxuchen 时间: 2011-11-9 21:39

如果对在体细胞进行去分化会否影响组织活性，是不是对ips或者其他干细胞做cell threapy的成瘤性有借鉴效果，感觉这方面可以做文章啊

作者: tjbone 时间: 2011-11-10 12:27

去分化研究非常有用，在肿瘤化生中表现的更为明显！！！！

作者: 千细胞 时间: 2011-11-11 23:24

其实现有的诱导分化实验在动物模型上进行功能验证，绝大部分都是取得特殊细胞类型的干/祖细胞，主要是两方面的因素：1是干/祖细胞有强的增殖能力和存活能力，能在一定程度上更加持续有效；2 利用体内的微环境刺激，结合机体整个的调节信息，干/祖细胞能更容易分化为所需的功能细胞并行使功能。
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文章中提及“未分化细胞诱导分化再去分化”，还要仔细看看再做评论

作者: jindong1006 时间: 2012-2-10 22:29

学习了，这种思路如果用在一些老的课题上再进行研究，应该会有很大的影响力。# }$ L" t" ^$ L

作者: jindong1006 时间: 2012-2-22 09:09

非常喜欢这个思路，给我的课题带来了新的切入点，支持干细胞之家！加油！

作者: 雁南飞 时间: 2012-2-22 10:49

一把双刃剑——去分化的细胞更原始了，具备更高的分化潜能和更长存活时间，因此可能具有更好的疗效；但与此同时，向治疗目的无关的方向分化更多更强了，增加了安全性风险。是好是坏，还要case by case才行。

作者: 一一 时间: 2012-2-22 11:24

干细胞分化后，可能会使某些基因打开，也可能某类蛋白发生甲基化，导致信号传导发生改变，而我更关心的是研究者怎么去分化的？去分化后DNA，蛋白发生了什么变化？如果按结论提示，二分化导致干细胞回归比最初状态还要原始的状态，难道是把某些物质去掉了？为什么呢？

作者: xiaoyurly 时间: 2012-2-22 11:25

干细胞移植治疗中一个十分重要也很基础的问题就是干细胞在宿主组织内的存活，直接影响其治疗效果。有很多研究者曾尝试不同的方法来提高干细胞在病灶区的存活率，比如转基因法、生长因子、热击、缺氧缺血等各种预处理法等等，这样一个先分化再转分化的过程也能实现存活率大大增强，挺神奇挺不可思议的，通过这种方法是强化了De-MSC向神经分化的“记忆”功能么？记得有些iPS的文章曾报道iPS在自发分化时极容易分化成其来源的细胞类型，可能有相似之处。

作者: fguw 时间: 2012-3-1 14:45

回复 lianzhimin 的帖子

这个比较还是很恰当的，：）

作者: fguw 时间: 2012-3-1 14:46

回复 lianzhimin 的帖子( l! y* M2 n- I5 ~: }* q) y! l
# I2 N& q, Y7 v6 w2 A2 Z7 U9 o
这个比喻还是很恰当的，：）

作者: fguw 时间: 2012-3-1 14:49

回复 lianzhimin 的帖子1 ~4 @: ?$ [& d b

这个比较还是很恰当的，：）

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