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标题: niche（环境）改变干细胞命运！ [打印本页]

作者: hcluo 时间: 2011-1-21 18:58 标题: niche（环境）改变干细胞命运！

niche与干细胞的关系一直受人关注。不知道有哪位高人正在做这个方面的研究，是不是干细胞在不同的niche会得到不同的终末分化，敬请指教啊！niche决定干细胞的命运，不是很认同，个人觉得niche可能存在改变干细胞的命运的作用，而只有干细胞自身才起主导作用。

作者: luoziwei 时间: 2011-1-21 20:26

niche的作用好像是使某个干细胞能接受特定的分化信号，一旦接受这个信号了，剩下的就看干细胞自身自灭了。

作者: evial 时间: 2011-1-21 21:14

niche的作用还是很大的，当然干细胞本身也是有讲究的，胚胎干细胞是全能的，在不同niche分化成不同，但是多能和定向的一些干细胞就没那么神通广大多了，限于某些分化类型细胞

作者: 临床干细胞 时间: 2011-1-21 21:47

我也要做这方面了，有相关的经典论文推荐吗

作者: sunsong7 时间: 2011-1-21 21:50

本帖最后由 sunsong7 于 2011-1-21 21:56 编辑

干细胞壁龛（niche）是一个用于描述“锚定干细胞并调控其处于G0期”微环境的一个非常宽松科学术语（或假说），这个微环境可以是体内（in vivo）也可以是体外（in vitro），niche为干细胞提供一个保护性微环境，不受外部诱导分化因素的影响而维持干细胞未分化状态。
niche概念涵盖的范围也非常宽泛，包括干细胞之间的相互作用、干细胞与已分化的邻近细胞之间的相互作用, 干细胞与粘附因子间的相互作用，细胞外基质成分、氧气张力生长因子、细胞因子的作用，以及导致微环境pH、离子强度（如Ca2+ 浓度）代谢物等物理化学性质改变的因素, ATP也很重要，这些因素可以通过与干细胞发生直接或间接的作用，从而调控干细胞，niche信号的变化可引起干细胞命运的改变。干细胞与niche之间相互的给出的信号在发育期和成体维持期也许是完全相反的，在机体发育期niche决定干细胞的命运，在成体维护期niche改变干细胞的命运。

作者: glasshour 时间: 2011-1-21 21:51

昨天看一关于线虫germ cell发育的文章$ P% K- e+ I5 K( H5 P6 ` w1 O
里面有讲细胞的分化主要是激素作用EGF-like grow factor
文中的讲解说明是由临近细胞分泌激素
我想，如果一个细胞换了一个环境，接收到的激素不同，分化也就不一样了
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另，还有一点很让我吃惊的是在线虫里面细胞周期的紊乱是不影响细胞分化的; O3 V5 l4 D1 `/ ?% n# f" t
由此也证明了细胞分化是由一个signal来起作用

作者: xiao6tao 时间: 2011-1-21 21:52

niche主要包括一些信号因子，干细胞产生，但是作用于干细胞。微环境的改变会影响干细胞的分化，不同的微环境分化成不同类型细胞或组织甚至成为癌干细胞

作者: sunsong7 时间: 2011-1-21 22:21

本帖最后由 sunsong7 于 2011-1-21 22:22 编辑

也可以换个思维来理解干细胞niche，从宏观层面每个生命个体都可以描述为“干细胞”，那么人类生存的环境就是“niche”，比喻虽不一定恰当，如此一来在体内干细胞的行为可以用社会行为学的一些准则来解释：“人之初，性本善，性相近，习相远；”用现代语言描述就是：环境影响行为，行为养成习惯；习惯塑造性格，性格决定选择；选择决定方向，方向决定命运。再譬如犯罪问题说到底“滋生罪犯的土壤才是真正的犯罪！”，今天的社会环境即便把克隆希特勒出来引发第三次世界大战可能性微乎其微，环境决定或改变命运。! e/ p* ~. a- E# |6 z

作者: hughliang 时间: 2011-1-21 23:42

本帖最后由 hughliang 于 2011-1-21 23:55 编辑 ) s- E& k# k. H5 ]3 h; g9 R. E
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推荐一篇cancer cell的文献：[attach]20757[/attach]
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人CD34+细胞转染MLL-AF9融合基因能在NOD/SCID小鼠诱导发生急性白血病，但使用不同的细胞因子或小鼠品系能诱导发生特定的急性髓系白血病、淋巴细胞白血病或双表型白血病，说明微环境对多潜能干细胞定向分化发挥诱导作用。

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作者: 张也行 时间: 2011-1-22 00:28

本帖最后由张也行于 2011-1-22 00:37 编辑 * `0 H7 B: B; n; s

回复 sunsong7 的帖子
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很佩服老狼的博学。
想请教你一个问题：niche决定干细胞的命运，那么谁决定niche的命运，niche从何而来？
干细胞和niche之间是否存在一种相互作用，相互决定的关系？4 W2 ?, Q7 x9 y* G6 x3 ]) T8 x
请用实证证明你的观点

作者: manybit 时间: 2011-1-22 08:43

脂肪干细胞培养有微环境吗？为什么脂肪干细胞培养不要饲养层？

作者: linchee 时间: 2011-1-22 10:21

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我觉得把stem cell和niche分开讨论就不太好，干细胞及其周边其他细胞，基质等之间的相互作用就是微环境内部的反应，微环境是整体？

作者: 张也行 时间: 2011-1-22 11:31

回复 linchee 的帖子/ I( L: Y$ F6 x! H/ c$ u
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虽然他们之间是一个整体，但是他们之间应该是有相互作用的。我觉得这种作用是研究干细胞分化，自我更新等机制的关键。并且，环境的形成是需要条件的，了解这些条件可以帮助更好的在体外维持干细胞的特性。个人见解... ...

作者: xiao6tao 时间: 2011-1-22 12:22

我觉得niche是一种存在的东西，包括细胞与细胞间的相互作用，一些分泌表型因子，个人觉得niche依靠干细胞，没有干细胞就没有大部分niche

作者: sunsong7 时间: 2011-1-22 18:09

本帖最后由 sunsong7 于 2011-1-22 18:15 编辑

张也行发表于 2011-1-22 00:28 ! I* y# s/ z5 g# j/ [
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很佩服老狼的博学。

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It’s a big question,  老狼试着回答一下9 u  N! y4 Z/ r9 t4 \
关于niche从何而来？答：胚胎干细胞的niche最初母体子宫提供的，成体干细胞的niche应该是自己搭建的；% P, L$ m; i' |' J5 O1 b# ?/ D
谁决定niche的命运？答：个人认为个体自身条件、生存环境和个体生活方式三方面共同决定niche的命运，
1）个体自身条件包括年龄、性别、遗传条件、家族病史、既往病史、身体条件（体格、体质以及精神、心理、生理疾病等）等，个体自身条件构成了决定niche命运内在因素；
2）生存环境如大气环境、水环境、生物环境、地质和土壤环境和其他自然环境，居住环境、工作环境、交通环境、文化环境和其他社会环境等，环境因素构成决定niche命运的外在因素；
4）生活方式是调节机体内部niche适应外界环境的主动干预方式，生活方式包括饮食习惯、工作习惯、休息习惯、运动习惯、用药习惯、吸烟饮酒习惯等等，不良的生活习惯会对niche构成损害；8 }8 i7 @, O" N' i7 G4 z
5）环境中各种物理、化学和生物因素和机体中进行交流和互动，机体为了生存不断调整内部环境以适应外界环境的挑战，从而微环境（niche）与宏观环境之间建立动态的平衡；, L5 V5 C5 L' @2 _6 V1 h8 H9 c
6）适当的环境因素刺激niche会做出响应形成新的平衡，保护干细胞不受伤害；过度的环境刺激会突破niche的调节限度，对干细胞构伤害从而引发疾病，此时需要有效的医学干预才能在新的机体条件达成新的平衡。
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最后一个问题：干细胞和niche之间是否存在一种相互作用，相互决定的关系？请用实证证明你的观点
答：一方面干细胞的遗传紊乱会破坏niche，譬如血管由内至外由内皮细胞、平滑肌细胞、干细胞构成，正常的平衡状态是血管组织为干细胞提供niche保护干细胞，干细胞不断置换凋亡的内皮细胞和平滑细胞保持血管平滑和运动功能，当炎症因素造成血管组织过度损伤，干细胞无法完成对血管细胞的补充和修复，同时造成niche环境恶化造成干细胞功能改变使血管纤维化，变得僵硬粗糙，从而引起高血压。癌细胞导致新生血管是干细胞改变niche的另一实例，在此不多叙述。0 k/ l  G( n1 ]" E, E; y
至于niche造成干细胞命运改变的极端实例也是癌症，肿瘤细胞在胚胎性微环境中倾向于有序的分化发育，胚胎干细胞在非胚胎性微环境中倾向于恶变为肿瘤细胞。3 `- L$ N0 e+ b. J
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此外：老狼认为“cancer——good cells in bad niche”,  解决癌的钥匙就在niche，可以考虑在体外模拟niche让癌细胞“归零”或者将癌细胞锚定并控制在G0期。

作者: sunsong7 时间: 2011-1-22 19:33

No place like home: anatomy and function of the stem cell niche

D. Leanne Jones & Amy J. Wagers

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Nature Reviews Molecular Cell Biology 9, 11-21 (January 2008) | doi:10.1038/nrm2319
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Stem cells are rare cells that are uniquely capable of both reproducing themselves (self-renewing) and generating the differentiated cell types that are needed to carry out specialized functions in the body. Stem cell behaviour, in particular the balance between self-renewal and differentiation, is ultimately controlled by the integration of intrinsic factors with extrinsic cues supplied by the surrounding microenvironment, known as the stem cell niche. The identification and characterization of niches within tissues has revealed an intriguing conservation of many components, although the mechanisms that regulate how niches are established, maintained and modified to support specific tissue stem cell functions are just beginning to be uncovered.5 S% T. b+ E+ I1 ~! y2 B
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The niche is a complex and dynamic structure that transmits and receives signals through cellular and acellular mediators. This schematic depicts a hypothetical niche composite, which summarizes known components of previously described mammalian and non-mammalian niches: the stem cell itself, stromal cells, soluble factors, extracellular matrix, neural inputs, vascular network and cell adhesion components. It is important to note that although many niche components are conserved, it is unlikely that every niche necessarily includes all of the components listed. Instead, niches are likely to incorporate a selection of these possible avenues for communication, specifically adapted to the particular functions of that niche, which might be to provide structural support, trophic support, topographical information and/or physiological cues.
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Wnt signalling can promote cell proliferation, such as self-renewal of haematopoietic stem cells (HSCs) (a) or proliferation of transit amplifying cells within intestinal crypts (not shown). Within some tissues, however, Wnt signalling directs the differentiation of specific cell lineages, such as hair follicle precursors (b), rather than promoting self-renewal of the multipotent stem cells from the follicular bulge. See the main text and Table 1 for more details. ANG1, angiopoietin-1; BMP4, bone morphogenetic protein-4; EphR, ephrin receptor; GSK3β, glycogen synthase kinase-3β; LEF, lymphoid enhancer factor; OPN, osteopontin; TCF, T-cell factor; TIE2, angiopoietin-1 receptor.

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Stem cell deficiency or deregulation contributes to multiple human pathologies, and accumulating evidence suggests that therapeutic targeting of the stem cell niche may provide a novel and effective strategy for improving treatment of these disorders. a | For example, correction of ageing- or disease-associated alterations in the niche could be used to boost endogenous stem cell number or function, and thereby improve tissue function17, 19, 115. b | Likewise, enhancing supportive niche function during transplantation could improve the efficiency of engraftment or accelerate stem cell reconstitution, perhaps reducing the number of stem cells needed for effective tissue reconstitution115. c | In addition, because the niche can have an important role in influencing stem cell fate decisions19, 70, as well as promoting stem cell self-renewal, appropriate modification of signals from the niche could be used to alter the outcomes of stem cell differentiation to favour production of a needed cell type or inhibit production of a detrimental one. d | Finally, in light of accumulating evidence suggesting that tumour-propagating cancer stem cells are dependent on signals from their niche22, 23, 114, just like their non-malignant counterparts, therapeutic ablation of components of the cancer stem cell niche could provide a novel strategy to remove tumour support factors, and thus achieve cancer remission.. `% [4 T; @/ o6 s! E

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作者: sunsong7 时间: 2011-1-22 19:46

本帖最后由 sunsong7 于 2011-1-22 19:52 编辑
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Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors

PNAS 2007 104 (39) 15418-15423; published ahead of print September 19, 2007, doi:10.1073/pnas.0707210104

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Abstract
Human colonic epithelial cell renewal, proliferation, and differentiation are stringently controlled by numerous regulatory pathways. To identify genetic programs of human colonic epithelial cell differentiation in vivo as well as candidate marker genes that define colonic epithelial stem/progenitor cells and the stem cell niche, we applied gene expression analysis of normal human colon tops and basal crypts by using expression microarrays with 30,000 genes. Nine hundred and sixty-nine cDNA clones were found to be differentially expressed between human colon crypts and tops. Pathway analysis revealed the differential expression of genes involved in cell cycle maintenance and apoptosis, as well as genes in bone morphogenetic protein (BMP), Notch, Wnt, EPH, and MYC signaling pathways. BMP antagonists gremlin 1, gremlin 2, and chordin-like 1 were found to be expressed by colon crypts. In situ hybridization and RT-PCR confirmed that these BMP antagonists are expressed by intestinal cryptal myofibroblasts and smooth muscle cells at the colon crypt. In vitro analysis demonstrated that gremlin 1 partially inhibits Caco-2 cell differentiation upon confluence and activates Wnt signaling in normal rat intestinal epithelial cells. Collectively, the expression data set provides a comprehensive picture of human colonic epithelial cell differentiation. Our study also suggests that BMP antagonists are candidate signaling components that make up the intestinal epithelial stem cell niche.

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Graphical view of human colon intestinal epithelial cell development and stem cell niche maintenance. Only genes with significant differential expression in paired t test (P < 0.05) are listed. ISEMF, intestinal subepithelial myofibroblast; SMC, smooth muscle cell.
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全文：http://www.pnas.org/content/104/39/15418.full

作者: sunsong7 时间: 2011-1-22 19:59

本帖最后由 sunsong7 于 2011-1-22 20:01 编辑 ' M. q9 l% l. T7 ~2 w% q' e

Counting human somatic cell replications: Methylation mirrors endometrial stem cell divisions

PNAS December 6, 2005 vol. 102 no. 49 17739-17744

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Cell proliferation may be altered in many diseases, but it is uncertain exactly how to measure total numbers of divisions. Although it is impossible to count every division directly, potentially total numbers of stem cell divisions since birth may be inferred from numbers of somatic errors. The idea is that divisions are surreptitiously recorded by random errors that occur during replication. To test this “molecular clock” hypothesis, epigenetic errors encoded in certain methylation patterns were counted in glands from 30 uteri. Endometrial divisions can differ among women because of differences in estrogen exposures or numbers of menstrual cycles. Consistent with an association between mitotic age and methylation, there was an age-related increase in methylation with stable levels after menopause, and significantly less methylation was observed in lean or older multiparous women. Methylation patterns were diverse and more consistent with niche rather than immortal stem cell lineages. There was no evidence for decreased stem cell survival with aging. An ability to count lifetime numbers of stem cell divisions covertly recorded by random replication errors provides new opportunities to link cell proliferation with aging and cancer. " M- N% c+ b& F2 R
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Stem cell niche. Stem cells are defined by their location within the niche, and their numbers are constant. After division, cells that leave the niche differentiate and eventually die. Niche stem cell lineages may either expand or become extinct, because stem cell division may be asymmetric (one stem and one differentiated daughter) or symmetric (two stem or two differentiated daughter cells). The exact size of the niche and extent of symmetric divisions are uncertain, because a variety of combinations are consistent with the experimental data (see table). A large niche with frequent symmetric division is equivalent to a smaller niche with less frequent symmetric division. Eventually all current-day niche stem cell lineages are lost except one, which recurs with a median interval of ≈10,000 divisions. Below are CSX endometrial gland simulations that assume 64 stem cells, P 1 of 0.98, a methylation error rate of 4.5 × 10-5, and a demethylation error rate of 5 × 10-6 per CpG site per division. Smaller or larger niches as in the table have similar outcomes (see Supporting Text). The gray line simulates nulliparous women (no live births) with one division per week before menarche, one division per day between ages 12 and 52, and one division per week after menopause. Multiparity (blue line) is simulated with 0.75 divisions per day between menarche and menopause. Obesity (red line) is simulated with 1.25 divisions per day after menarche. Dotted lines include 95% of simulated gland outcomes indicating the scatter expected from stochastic errors and stem cell turnover.
全文：http://www.pnas.org/content/102/49/17739.full

作者: 张也行 时间: 2011-1-22 22:01

本帖最后由张也行于 2011-1-22 22:08 编辑

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老狼认为“cancer——good cells in bad niche”, 解决癌的钥匙就在niche，可以考虑在体外模拟niche让癌细胞“归零”或者将癌细胞锚定并控制在G0期。

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癌细胞的niche是CSC产生的吗？如果是的话那么改变cancer的niche就是改变CSC，CSC是肿瘤始发和复发的关键细胞，没有了CSC自然就没有了niche。所以将癌细胞移到一个good niche里的话，怎么保证是niche驯化CSC，而不是反过来CSC腐化niche呢？

作者: sunsong7 时间: 2011-1-22 22:15

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CSC仍是一种假说，老狼更愿意相信癌起始细胞（CIC）是由成体干细胞在恶劣的niche中自发产生的内源性诱导多能干细胞（Endogenous iPS），内源性iPS在成体干细胞搭建的niche中命运出现了不确定性，其中一种可能就是恶变为肿瘤。

作者: 张也行 时间: 2011-1-23 08:58

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那么你觉得在肿瘤转移过程中，新的病灶的niche除了CSC还有谁产生呢？

作者: xiao6tao 时间: 2011-1-23 10:29

cancer——good cells in bad niche很到位！

作者: sunsong7 时间: 2011-1-23 11:40

张也行发表于 2011-1-23 08:58 ) f3 N$ _/ m% \+ A
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那么你觉得在肿瘤转移过程中，新的病灶的niche除了CSC还有谁产生呢？

非常好的问题，niche的作用是调控干细胞处在G0，新迁移来的肿瘤细胞（所谓的CSC）住到原先成体干细胞修建的niche中会觉得水土不服，进入细胞周期通过快速生长搭建了属于自己的niche。

作者: 张也行 时间: 2011-1-23 11:52

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那么“cancer——good cells in bad niche”是否应该加上一句"cancer——bad cells corrupt good niche"呢？

作者: sunsong7 时间: 2011-1-23 11:54

张也行发表于 2011-1-23 11:52 7 F* |" u. G e2 K3 y4 A
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5 t+ ~/ K, _) E5 g, x4 O那么“cancer——good cells in bad niche”是否应该加上一句"cancer——bad cells ...

good idea

作者: 张也行 时间: 2011-1-23 11:57

本帖最后由张也行于 2011-1-23 11:58 编辑 $ F1 H& M1 f& a) N, U
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跟老狼讨论里这么久，越来越发现linchee的观点“niche和干细胞是一个整体”的重要性。重要的不是二者谁决定谁，那样还是把二者分开理解，真正重要的是二者之间的作用关系。

作者: zhangjinxy 时间: 2011-2-11 10:17

最近看了很多这方面的paper，发表点看法：在动物体内，niche的命运是胚胎发育时期自分泌或邻近胚层旁分泌的诱导信号来决定干细胞的命运，分泌的诱导信号之间通过广泛的cross-talk，来决定干细胞的分化方向。精确的cross-talk的丧失会导致发育异常和先天性疾病的发生。

作者: varing 时间: 2011-2-22 11:58

回复张也行的帖子
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我觉得niche只能说是影响干细胞或其他细胞分化命运、自我增殖等的细胞环境，就包括细胞或者其他的胞外成分。多细胞生物作为细胞共同体，不能笼统的说谁决定谁的命运。像SSC（精原干细胞）在体内其self-renewal和proliferation是靠周围环境周围细胞分泌的细胞因子来帮助调控的，如sertoli cell 分泌GDNF、FGF、EGF等，这些激素和因子影响干细胞分增殖分化等，这就是周围的支持细胞来影响干细胞的命运，而sertoli cell的因子分泌又由其他的激素来调控如脑垂体分泌的促性腺分泌激素等的调控，肯定也还有曲细精管的外周环境（外周细胞、胞外基质等）来影响。

作者: askage 时间: 2011-2-22 13:08

回复 sunsong7 的帖子
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我最近也在头疼。实验老是不顺利。培养的MSC细胞总是不那么理想。想找点基础资料看看。老狼兄弟有没得综述性的资料“如何维持干细胞的干性”

作者: wxiouno4 时间: 2011-4-7 19:51

牛.......

作者: embryonic12 时间: 2011-4-7 20:17

整个有机体就是一个大的nich呀，他是无数个小nich的nich，当然其中间还可有多级

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