企业邮箱
天下生命科学前沿动态周报（四十八）
（7.11-7.17/2011）
一竞技国际集团:陶国新
主要内容：裸鼠移植人神经干细胞减轻由辐射引起的认知功效障碍；胎儿期和哺乳期营养状态影响成年后的基因表达；新化合物通过阻断对高氧化压力的顺应来选择性杀死癌细胞；诱导多醒目细胞的表观遗传影象；小RNA指导人纤维母细胞转酿成神经元；多能神经干细胞天生大脑中的神经元和胶质细胞。
焦点动态：新化合物通过阻断对高氧化压力的顺应来选择性杀死癌细胞。
1. 裸鼠移植人神经干细胞减轻由辐射引起的认知功效障碍
【动态】
治疗脑癌的头部放疗导致的认知能力逐渐变弱部分缘故原由可能是神经干细胞耗竭。美国科学家通过辐照无胸腺裸鼠两天后在海马区内移植人神经干细胞来磨练干细胞替换战略在搪塞辐射引起的认知能力削弱方面的潜力。在辐照后1个月和4个月测定认知体现、人神经干细胞的存活状态和表型效果。移植人神经干细胞的辐照大鼠认知功效的削弱显着比伪装移植的辐照大鼠少，体现与未辐照的比照大鼠无可识别的差别。无私见的立体丈量显示移植细胞在移植后1和4个月划分存活23%和12%。 移植的细胞普遍迁徙，向神经胶质和神经元细胞分解，并且表达调理行动的细胞骨架相关卵白（Arc），提醒其能够在功效上整合进海马区。这些数据批注人神经干细胞提供了一种有希望的战略来恢复受辐照动物的认知功效。
【点评】
此类实验用人造的无免疫力的裸鼠试验干细胞移植的效果，可以看到在没有免疫倾轧的情形下移植细胞的体现，可是对临床治疗险些没有任何参考价值。若是在具有自身免疫的正常动物身上举行干细胞移植，很可能移植的细胞基础无法存活，更不要说进一步分解和功效整合；并且被倾轧的细胞在移植部位还可能引起严重效果。
【参考论文】Cancer Research, 2011; 71 (14): 4834 DOI: 10.1158/0008-5472.CAN-11-0027
Human Neural Stem Cell Transplantation Ameliorates Radiation-Induced Cognitive Dysfunction
M. M. Acharya, L.-A. Christie, M. L. Lan, et al.
Cranial radiotherapy induces progressive and debilitating declines in cognition that may, in part, be caused by the depletion of neural stem cells. The potential of using stem cell replacement as a strategy to combat radiation-induced cognitive decline was addressed by irradiating athymic nude rats followed 2 days later by intrahippocampal transplantation with human neural stem cells (hNSC). Measures of cognitive performance, hNSC survival, and phenotypic fate were assessed at 1 and 4 months after irradiation. Irradiated animals engrafted with hNSCs showed significantly less decline in cognitive function than irradiated, sham-engrafted animals and acted indistinguishably from unirradiated controls. Unbiased stereology revealed that 23% and 12% of the engrafted cells survived 1 and 4 months after transplantation, respectively. Engrafted cells migrated extensively, differentiated along glial and neuronal lineages, and expressed the activity-regulated cytoskeleton-associated protein (Arc), suggesting their capability to functionally integrate into the hippocampus. These data show that hNSCs afford a promising strategy for functionally restoring cognition in irradiated animals.
2. 胎儿期和哺乳期营养状态影响成年后的基因表达
【动态】
短暂的情形影响，像围产期营养压力，可能诱发一连终生的代谢不良症状，这意味着表观遗传修饰在此历程中起主要作用。法国科学家最近研究了在妊娠和哺乳期母老鼠营养不良对DNA甲基化和瘦素基因表达的影响，瘦素基因在协调哺乳动物生物学的许多方面与营养状态的关系上起主要调理作用。效果显示喂低卵白食物的老鼠生的子女比比照组的老鼠体重更轻，食量更大。这些转变一连终生与实验组饥饿老鼠的低水平的瘦素mRNA和卵白有关，突显了母代卵白营养缺乏影响了子女成年时进食和能量消耗之间的平衡。并且，这种营养压力导致瘦素启动子上的CpGs失去甲基，引起瘦素表达动力学方面永世性的特殊转变，体现为实验组老鼠比比照组对食物有更强的反应。这一研究是将短暂的情形影响和永世性表型转变相联系的分子机理的例子。
【点评】
这一研究在老鼠身上看到了后天营养状态通过表观遗传修饰影响了个体胎儿的基因表达，改变了成年个体的代谢状态。
【参考论文】FASEB Journal, June 13, 2011 fj.11-181792; published ahead of print
Perinatal Undernutrition Affects the Methylation and Expression of the Leptin Gene in Adults: Implication for the Understanding of Metabolic Syndrome
C Jousse, L Parry, S Lambert-Langlais, et al.
Transient environmental influences, such as perinatal nutritional stress, may induce deleterious metabolic symptoms that last for the entire life of individuals, implying that epigenetic modifications play an important role in this process. We have investigated, in mice, the consequences of maternal undernutrition during gestation and lactation on DNA methylation and expression of the leptin gene, which plays a major regulatory role in coordinating nutritional state with many aspects of mammalian biology. We show that animals born to mothers fed a low-protein-diet (F1-LPD group) have a lower body weight/adiposity and exhibit a higher food intake than animals born to mothers fed a control diet (F1-CD group). These modifications persisted throughout life and were associated with lower levels of leptin mRNA and protein in starved F1-LPD mice, emphasizing that maternal protein-undernutrition affects the balance between food intake and energy expenditure in adults. Moreover, this nutritional stress resulted in the removal of methyls at CpGs located in the promoter of leptin, causing a permanent specific modification in the dynamics of the expression of leptin, which exhibits a stronger induction in the F1-LPD than in F1-CD mice in response to a meal. This study is an example of a molecular rationale linking transient environmental influences to permanent phenotypic consequences.
3. 新化合物通过阻断对高氧化压力的顺应来选择性杀死癌细胞
【动态】
激活癌基因的突变和失活肿瘤抑制基因的突变所驱动的细胞恶变导致经常与升高的细胞压力（如氧化、复制、代谢和卵白毒性压力、DNA损伤）有关的细胞失调。为了生涯，癌细胞必需顺应这种压力，效果癌细胞可能变得依赖那些寻常在正常细胞中不起云云要害作用的非癌基因。因此，在表型变换时针对这类非癌基因依赖性可能造成人为的致命相互作用和选择性癌细胞殒命。使用基于细胞的小分子筛选和定量的卵白组学要领客观地识别出能够选择性杀死癌细胞而非正常细胞的小分子。不管p53是何状态，来自胡椒的自然产品荜茇酰胺在癌细胞和设计带有癌基因型的通俗细胞中都能增添活性氧自由基水平和细胞凋亡，但它对快破碎或者慢破碎的基本正常细胞作用很小。在异种移植肿瘤模子老鼠中视察到荜茇酰胺显着的抗肿瘤作用，而对正常老鼠无显着毒性。并且，荜茇酰胺强力抑制老鼠自觉形成的恶性乳腺肿瘤的生长和转移。该研究效果批注一种小分子能选择性地在有癌基因型的细胞中通过靶向在癌基因表达时爆发的应对转变引起的氧化压力的非癌基因依赖性来诱导该细胞凋亡。
【点评】
选择性阻断癌细胞对情形的顺应从而让情形因素引起癌细胞凋亡。该研究中的荜茇酰胺对处于高氧化压力下的癌细胞中的抗氧化酶在其浓度凌驾正常细胞中的水平时有抑制作用，从而选择性地诱导癌细胞在氧化压力下凋亡。这一点对研究一竞技再生物质的抗癌作用机理有启示。
【参考论文】Nature, 2011; 475 (7355): 231 DOI: 10.1038/nature10167
Selective killing of cancer cells by a small molecule targeting the stress response to ROS
Lakshmi Raj, Takao Ide, Aditi U. Gurkar, et al.
Malignant transformation, driven by gain-of-function mutations in oncogenes and loss-of-function mutations in tumour suppressor genes, results in cell deregulation that is frequently associated with enhanced cellular stress (for example, oxidative, replicative, metabolic and proteotoxic stress, and DNA damage). Adaptation to this stress phenotype is required for cancer cells to survive, and consequently cancer cells may become dependent upon non-oncogenes that do not ordinarily perform such a vital function in normal cells. Thus, targeting these non-oncogene dependencies in the context of a transformed genotype may result in a synthetic lethal interaction and the selective death of cancer cells. Here we used a cell-based small-molecule screening and quantitative proteomics approach that resulted in the unbiased identification of a small molecule that selectively kills cancer cells but not normal cells. Piperlongumine increases the level of reactive oxygen species (ROS) and apoptotic cell death in both cancer cells and normal cells engineered to have a cancer genotype, irrespective of p53 status, but it has little effect on either rapidly or slowly dividing primary normal cells. Significant antitumour effects are observed in piperlongumine-treated mouse xenograft tumour models, with no apparent toxicity in normal mice. Moreover, piperlongumine potently inhibits the growth of spontaneously formed malignant breast tumours and their associated metastases in mice. Our results demonstrate the ability of a small molecule to induce apoptosis selectively in cells that have a cancer genotype, by targeting a non-oncogene co-dependency acquired through the expression of the cancer genotype in response to transformation-induced oxidative stress.
4. 诱导多醒目细胞的表观遗传影象
【动态】
人诱导多醒目细胞看似很是像人胚胎干细胞。以色列科学家用两种遗传谱系追踪系统证实晰从人胰岛β细胞天生诱导多醒目细胞系。这些重组的细胞获得了多醒目细胞的标记并分解成三胚层。然而，从β细胞而来的诱导多醒目细胞(BiPSCs)在要害β细胞基因上维持开放的染色质结构，同时有一个奇异的DNA甲基化署名以区别于其他多醒目细胞。与胚胎干细胞和同基因的非β细胞来的iPSCs 相比，BiPSCs也显示了更高的体内体外分解成生产胰岛素的细胞的能力。其研究效果提醒表观遗传影象可能使BiPSCs更倾向于分解成生产胰岛素的细胞。这些发明证实人诱导多醒目细胞的体现型可能受其泉源细胞的影响，也提醒其受影响的分解潜力可能有利于细胞替换治疗。
【点评】
该研究的诱导多醒目细胞能够倾向性地分解成其泉源细胞，看似手艺前进，实则无奈之举，由于人们无法驾驭诱导多醒目细胞，不知道怎样创立生命的条件使诱导多醒目细胞能够正常分解成任何需要的细胞。别的，诱导多醒目细胞基因组的改变使其再也不是正常细胞，成为人造细胞。
【参考论文】Cell Stem Cell, 2011; 9 (1): 17 DOI:10.1016/j.stem.2011.06.007
Epigenetic Memory and Preferential Lineage-Specific Differentiation in Induced Pluripotent Stem Cells Derived from Human Pancreatic Islet Beta Cells
Ori Bar-Nur, Holger A. Russ, Shimon Efrat, Nissim Benvenisty.
Human induced pluripotent stem cells (HiPSCs) appear to be highly similar to human embryonic stem cells (HESCs). Using two genetic lineage-tracing systems, we demonstrate the generation of iPSC lines from human pancreatic islet beta cells. These reprogrammed cells acquired markers of pluripotent cells and differentiated into the three embryonic germ layers. However, the beta cell-derived iPSCs (BiPSCs) maintained open chromatin structure at key beta-cell genes, together with a unique DNA methylation signature that distinguishes them from other PSCs. BiPSCs also demonstrated an increased ability to differentiate into insulin-producing cells both in vitro and in vivo, compared with ESCs and isogenic non-beta iPSCs. Our results suggest that the epigenetic memory may predispose BiPSCs to differentiate more readily into insulin producing cells. These findings demonstrate that HiPSC phenotype may be influenced by their cells of origin, and suggest that their skewed differentiation potential may be advantageous for cell replacement therapy.
5. 小RNA指导人纤维母细胞转酿成神经元
【动态】
神经元的转录因子和进化上守旧的信号通路被发明是有助于神经元的形成。然而，小RNA在神经新生中的指导作用还不清晰。美国科学家最近发明miR-9* 和miR-124指导SWI/SNF-like BAF 染色质重塑复合体组分的转变，该历程对神经元分解和功效很主要。在靠近神经元祖细胞有丝破碎出口时，miR-9* 和miR-124抑制神经元祖细胞BAF 染色质重塑复合体的BAF53a 亚基。在有丝破碎出口之后，BAF53a 被BAF53b取代，BAF45a被 BAF45b 和 BAF45c取代，后者合并成为神经元特异的BAF复合体为有丝破碎后的功效所必需。由于miR-9* 和miR-124也控制多个调理神经元分解和功效的基因，他们以为这些小RNA可能与神经元运气有关。他们的研究显示人纤维母细胞中miR-9/9* 和miR-124的表达诱导其转酿成神经元，该历程受NEUROD2的增进。进一步加着迷经元的转录因子ASCL1 和 MYT1L提高了转化率和转化成的神经元的成熟，这其中只表达这些转录因子不表达miR-9/9*-124 的话是没有用果的。该研究体现涉及miR-9/9*-124的遗传线路对神经元运气决议有指导作用。
【点评】
小RNA指导人纤维母细胞转酿成神经元，展现了表观调控对细胞分解的控制。表观调控的研究将是比基因组研究更有适用价值的课题。
【参考论文】Nature, 2011; DOI:10.1038/nature10323
MicroRNA-mediated conversion of human fibroblasts to neurons
Andrew S. Yoo, Alfred X. Sun, Li Li, et al.
Neurogenic transcription factors and evolutionarily conserved signalling pathways have been found to be instrumental in the formation of neurons. However, the instructive role of microRNAs (miRNAs) in neurogenesis remains unexplored. We recently discovered that miR-9* and miR-124 instruct compositional changes of SWI/SNF-like BAF chromatin-remodelling complexes, a process important for neuronal differentiation and function. Nearing mitotic exit of neural progenitors, miR-9* and miR-124 repress the BAF53a subunit of the neural-progenitor (np)BAF chromatin-remodelling complex. After mitotic exit, BAF53a is replaced by BAF53b, and BAF45a by BAF45b and BAF45c, which are then incorporated into neuron-specific (n)BAF complexes essential for post-mitotic functions. Because miR-9/9* and miR-124 also control multiple genes regulating neuronal differentiation and function, we proposed that these miRNAs might contribute to neuronal fates. Here we show that expression of miR-9/9* and miR-124 (miR-9/9*-124) in human fibroblasts induces their conversion into neurons, a process facilitated by NEUROD2. Further addition of neurogenic transcription factors ASCL1 and MYT1L enhances the rate of conversion and the maturation of the converted neurons, whereas expression of these transcription factors alone without miR-9/9*-124 was ineffective. These studies indicate that the genetic circuitry involving miR-9/9*-124 can have an instructive role in neural fate determination.
6. 多能神经干细胞天生大脑中的神经元和胶质细胞
【动态】
神经元天生和胶质天生在成体哺乳动物大脑的分立的区域一连举行。一个尚未解决的基本问题是细胞天生是来自谱系限制的祖细胞照旧来自成体大脑中自我更新的多能神经干细胞。美国科学家的最新研究接纳遗传标记战略在成年迈鼠齿状回中追踪单个的、静止的、表达巢卵白的放射状胶质样前体细胞（RGL）�？寺∑饰龇⒚鞫嘀旨せ頡GL的方法，包括差池称和对称自我更新。体内的恒久谱系追踪显示有显着比例的克隆包括RGLs、神经元和星形胶质细胞，批注单个RGL能够自我更新同时举行多谱系分解。别的，在RGL中有条件地去除Pten一最先增进其激活和对称的自我更新，但最终导致星形胶质细胞的最终分解和成体海马区RGL的耗竭。该研究判断RGL为自我更新的多能神经干细胞，提供了体内成体神经干细胞特征的新看法。
【点评】
体内的克隆剖析展现自我更新和成体多能神经干细胞特征，关于神经新生历程有了进一步相识。
【参考论文】Cell, 2011; 145 (7): 1142 DOI:10.1016/j.cell.2011.05.024
In Vivo Clonal Analysis Reveals Self-Renewing and Multipotent Adult Neural Stem Cell Characteristics
Michael A. Bonaguidi, Michael A. Wheeler, Jason S. Shapiro, et al.
Neurogenesis and gliogenesis continue in discrete regions of the adult mammalian brain. A fundamental question remains whether cell genesis occurs from distinct lineage-restricted progenitors or from self-renewing and multipotent neural stem cells in the adult brain. Here, we developed a genetic marking strategy for lineage tracing of individual, quiescent, and nestin-expressing radial glia-like (RGL) precursors in the adult mouse dentate gyrus. Clonal analysis identified multiple modes of RGL activation, including asymmetric and symmetric self-renewal. Long-term lineage tracing in vivo revealed a significant percentage of clones that contained RGL(s), neurons, and astrocytes, indicating capacity of individual RGLs for both self-renewal and multilineage differentiation. Furthermore, conditional Pten deletion in RGLs initially promotes their activation and symmetric self-renewal but ultimately leads to terminal astrocytic differentiation and RGL depletion in the adult hippocampus. Our study identifies RGLs as self-renewing and multipotent neural stem cells and provides novel insights into in vivo properties of adult neural stem cells.