企业邮箱
天下生命科学前沿动态周报（六十五）
（11.7-11.13/2011）
一竞技国际集团:陶国新
主要内容：过表达dPGC-1延伸果蝇寿命 ；差别微情形中的肠干细胞之间的相互转换 ；脂肪细胞去除NCoR降低了PPARγ磷酸化增强了 PPARγ 的作用和胰岛素敏感性 ；生物钟造成表皮干细胞的异质性 ；磷酸酰甘油抑制伤风病毒A的熏染 ；用实验鼠的胚胎干细胞培育出脑垂体 。
焦点动态：过表达dPGC-1延伸果蝇寿命 。
1.过表达dPGC-1延伸果蝇寿命
【动态】
哺乳动物的PGC-1转录共激活物是其能量代谢，包括线粒体生物合成和呼吸作用的要害调理因子，这已体现在在包括神经退行性病变和心肌病变等许多病变中 。而美国科学家最新的研究批注果蝇PGC-1同系物（dPGC-1）过表达足以增添线粒体活性 。并且，在消化道的干细胞和祖细胞中组织特异性的过表达dPGC-1延伸了果蝇寿命 。过表达dPGC-1的长寿的果蝇肠道年岁相关的转变推迟了，因而增进了老龄果蝇组织的稳固性 。总而言之，这些效果批注dPGC-1能够在个体组织的细胞转变和整个有机体双重水平上延缓朽迈 。这些发明指出一种可能性，即在像肠这样的更新很快的组织中PGC-1活性的转变可能是哺乳动物长寿的主要决议因素 。
【点评】
这一研究效果批注PGC-1作用增强提高了果蝇线粒体的活性和作用，延伸了果蝇的寿命 。关于研究哺乳动物尤其是人类的朽迈和抗衰总是主要的借鉴 。
【参考论文】
Cell Metabolism, 2011; 14 (5): 623 DOI:10.1016/j.cmet.2011.09.013
Modulation of Longevity and Tissue Homeostasis by the Drosophila PGC-1 Homolog
Michael Rera, Sepehr Bahadorani, Jaehyoung Cho, et al.
In mammals, the PGC-1 transcriptional coactivators are key regulators of energy metabolism, including mitochondrial biogenesis and respiration, which have been implicated in numerous pathogenic conditions, including neurodegeneration and cardiomyopathy. Here, we show that overexpression of the Drosophila PGC-1 homolog (dPGC-1/spargel) is sufficient to increase mitochondrial activity. Moreover, tissue-specific overexpression of dPGC-1 in stem and progenitor cells within the digestive tract extends life span. Long-lived flies overexpressing dPGC-1 display a delay in the onset of aging-related changes in the intestine, leading to improved tissue homeostasis in old flies. Together, these results demonstrate that dPGC-1 can slow aging both at the level of cellular changes in an individual tissue and also at the organismal level by extending life span. Our findings point to the possibility that alterations in PGC-1 activity in high-turnover tissues, such as the intestine, may be an important determinant of longevity in mammals.
2.差别微情形中的肠干细胞之间的相互转换
【动态】
肠上皮干细胞的识别和定位一直是个需要实质研究的事情 。+4微情形中的细胞循环很慢，保存标记，而另一种干细胞微情形位于腺窝底部，内住窝底柱状细胞（CBC） 。CBC差别于+4细胞，二者之间的关系尚不清晰，但二者都能爆发所有肠上皮细胞系 。美国科学家最近发明Hopx，一种非典范同源盒卵白，是+4细胞的新的特异性标记 。表达Hopx的细胞能够爆发CBC以及所有成熟的肠上皮细胞系 。反之，CBC也能够爆发Hopx阳性的+4细胞 。这些发明批注在他们的微情形中活跃的和静止的干细胞之间保存一种双向的谱系关系 。
【点评】
该研究意外发明破碎速率差别的两种肠干细胞能够相互爆发对方，竣事了谁是真正的肠干细胞的争论 。
【参考论文】
Science, 2011; DOI: 10.1126/science.1213214
Interconversion Between Intestinal Stem Cell Populations in Distinct Niches
N. Takeda, R. Jain, M. R. LeBoeuf, et al.
Intestinal epithelial stem cell identity and location has been the matter of substantial research. Cells in the +4 niche are slow-cycling and label retaining, while a distinct stem cell niche located at the crypt base is occupied by crypt base columnar (CBC) cells. CBCs are distinct from +4 cells, and the relationship between them is unknown, though both give rise to all intestinal epithelial lineages. We demonstrate that Hopx, an atypical homeobox protein, is a novel and specific marker of +4 cells. Hopx-expressing cells give rise to CBCs and all mature intestinal epithelial lineages. Conversely, CBCs can give rise to +4 Hopx positive cells. These findings demonstrate a bidirectional lineage relationship between active and quiescent stem cells in their niches.
3.脂肪细胞去除NCoR降低了 PPARγ 磷酸化增强了 PPARγ 的作用和胰岛素敏感性
【动态】
胰岛素抗性、组织发炎和脂肪组织功效障碍是肥胖和2型糖尿病的特征 。美国和瑞典的科学家建设了敲除脂肪细胞特异性核受体辅抑制物（NCoR）的老鼠模子（AKO）来研究脂肪细胞生物学、葡萄糖和胰岛素体内平衡中NCoR的功效 。除了肥胖增多，AKO老鼠的葡萄糖耐受性提高了，肝脏、肌肉和脂肪中胰岛素敏感性增强了 。脂肪组织巨噬细胞浸润和炎症镌汰了 。AKO老鼠脂肪组织中PPAR响应基因上调，CDK5 介导的 PPAR 273号丝氨酸磷酸化镌汰，爆发了却构上处于活化状态的PPAR 。由此判断NCoR是一种适配卵白，作用是增强CDK5联系和磷酸化PPAR的能力 。脂肪细胞NCoR
的主导作用是反抑制PPAR 和增进PPAR 273号丝氨酸磷酸化, 因而 去除NCoR导致 脂肪天生、炎症镌汰和全身胰岛素敏感性增强，模拟了TZD药物治疗的状态 。
【点评】
NCoR功效的剖析，有助于进一步相识肥胖和2型糖尿病的病理 。关于研发通过增强胰岛素敏感性手段的治疗2型糖尿病提供了新的思绪 。
【参考论文】
Cell, Volume 147, Issue 4, 815-826, 11 November 2011
Adipocyte NCoR Knockout Decreases PPARγ Phosphorylation and Enhances PPARγ Activity and Insulin Sensitivity
Pingping Li, WuQiang Fan, Jianfeng Xu, et al.
Insulin resistance, tissue inflammation, and adipose tissue dysfunction are features of obesity and Type 2 diabetes. We generated adipocyte-specific Nuclear Receptor Corepressor (NCoR) knockout (AKO) mice to investigate the function of NCoR in adipocyte biology, glucose and insulin homeostasis. Despite increased obesity, glucose tolerance was improved in AKO mice, and clamp studies demonstrated enhanced insulin sensitivity in liver, muscle, and fat. Adipose tissue macrophage infiltration and inflammation were also decreased. PPAR response genes were upregulated in adipose tissue from AKO mice and CDK5-mediated PPAR ser-273 phosphorylation was reduced, creating a constitutively active PPAR state. This identifies NCoR as an adaptor protein that enhances the ability of CDK5 to associate with and phosphorylate PPAR. The dominant function of adipocyte NCoR is to transrepress PPAR and promote PPAR ser-273 phosphorylation, such that NCoR deletion leads to adipogenesis, reduced inflammation, and enhanced systemic insulin sensitivity, phenocopying the TZD-treated state.
4.生物钟造成表皮干细胞的异质性
【动态】
鼠类表皮干细胞交替举行休眠和活跃周期，包管组织更新 。然而，在每轮形态爆发中只有一种干细胞亚群处于活跃期，意味着所有干细胞以差别反应状态共存 。西班牙瑞典和美国科学家用生物钟报告器老鼠模子证实支配职位的毛囊干细胞微情形包括处于生物钟相反相但共存的细胞群，他们在分解时期已形成响应内稳态线索的倾向 。焦点的生物钟卵白Bmal1以振荡方法调理干细胞调控基因的表达，以爆发先天活化倾向巨细差别的细胞群 。通已往除Bmal或Per1/2破损该卵白的平衡，划分导致休眠干细胞的一连积累或消除 。干细胞节律失调也会导致表皮提前朽迈和鳞状癌的镌汰 。他门的效果批注生物钟微调表皮干细胞的一时行为，该扰动影响内平衡和肿瘤爆发的诱因 。
【点评】
该研究效果意味着表皮干细胞的活化受到生物钟的控制，生物节律的破损导致表皮干细胞再生能力受影响，组织提前朽迈，更易诱发皮肤癌 。
【参考论文】
Nature, 2011; DOI: 10.1038/nature10649
The circadian molecular clock creates epidermal stem cell heterogeneity
Peggy Janich, Gloria Pascual, Anna Merlos-Suárez, et al.
Murine epidermal stem cells undergo alternate cycles of dormancy and activation, fuelling tissue renewal. However, only a subset of stem cells becomes active during each round of morphogenesis, indicating that stem cells coexist in heterogeneous responsive states. Using a circadian-clock reporter-mouse model, here we show that the dormant hair-follicle stem cell niche contains coexisting populations of cells at opposite phases of the clock, which are differentially predisposed to respond to homeostatic cues. The core clock protein Bmal1 modulates the expression of stem cell regulatory genes in an oscillatory manner, to create populations that are either predisposed, or less prone, to activation. Disrupting this clock equilibrium, through deletion of Bmal1 (also known as Arntl) or Per1/2, resulted in a progressive accumulation or depletion of dormant stem cells, respectively. Stem cell arrhythmia also led to premature epidermal ageing, and a reduction in the development of squamous tumours. Our results indicate that the circadian clock fine-tunes the temporal behaviour of epidermal stem cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis.
5. 磷酸酰甘油抑制伤风病毒A的熏染
【动态】
A型伤风病毒（IAV）是天下性的公共卫生问题，每年导致500,000人殒命 。棕榈� ；王 ；姿狨 ；视停≒OPG）是肺部外貌活性剂的次要因素，最近发明其有潜在的调理先天免疫的作用 。美国科学家的最新研究证实POPG是很强的IAV抗病毒剂 。在人体支气管上皮细胞作育中，POPG显著地调理IL-8的生产和IAV引起的细胞殒命 。这种脂类还抑制病毒对细胞膜的粘附及随后在MDCK细胞中的复制 。H1N1-PR8-IAV和H3N2-IAV两种病毒株与POPG有很高的亲和力但对结构类似的脂类 磷脂酰胆碱亲和力却很低 。在有POPG的情形下在老鼠鼻内接种H1N1-PR8-IAV显著抑制 了炎症细胞的浸润和支气管肺泡灌洗诱导的IFN-，以及熏染5天后肺部的病毒数目 。这些发明确认增补POPG 是一种潜在的治疗IAV熏染的主要的新要领 。
【点评】
该研究发明在肺部自然保存的一种脂类能够在细胞作育和动物模子中抑制伤风病毒熏染、炎症反应、病毒撒播和熏染引起的细胞殒命 。增补此类脂类有助于增强机体对伤风病毒的对抗力 。
【参考论文】
American Journal of Respiratory Cell and Molecular Biology, 2011; DOI: 10.1165/rcmb.2011-0194OC
Phosphatidylglycerol Suppresses Influenza A Virus Infection
M. Numata, P. Kandasamy, Y. Nagashima, et al.
Influenza A virus (IAV) is a worldwide public health problem causing 500,000 deaths each year. Palmitoyl-oleoyl-phosphatidylglycerol (POPG) is a minor component of pulmonary surfactant, which has recently been reported to exert potent regulatory functions upon the innate immune system. In this report we demonstrate that POPG acts as a strong anti-viral agent against IAV. POPG markedly attenuated IL-8 production and cell death induced by IAV in cultured human bronchial epithelial cells. The lipid also suppressed viral attachment to the plasma membrane and subsequent replication in MDCK cells. Two virus strains, H1N1-PR8-IAV and H3N2-IAV bind to POPG with high affinity but exhibit only low affinity interactions with the structurally related lipid palmitoyl-oleoyl-phosphatidylcholine. Intranasal inoculation of H1N1-PR8-IAV in mice, in the presence of POPG, markedly suppressed the development of inflammatory cell infiltrates and the induction of IFN- recovered in bronchoalveolar lavage, and viral titers recovered from the lungs after 5 days of infection. These findings identify supplementary POPG as a potentially important new approach for treatment of IAV infections.
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6.用实验鼠的胚胎干细胞培育出脑垂体
【动态】
脑垂体是位于大脑下部的一个内渗透器官，它渗透多种激素，在身体生长发育、调理血压、女性乳汁渗透等多方面都施展着主要作用 。这是一个很是重大的器官，若是功效受损也不易治疗 。日本科学家最近在特殊的三维作育情形中用实验鼠的胚胎干细胞培育出脑垂体，并且培育出的脑垂体在移植给原本脑垂体有缺陷的实验鼠后，能够正常渗透激素 。这批注医生也允许以用这种要领来治疗人类的相关疾病 。本次研究显示，关于那些脑垂体有缺陷而相关激素水平下降的实验鼠，若是植入人工培育的脑垂体，相关激素水平会泛起回升 。这显示了人工培育的脑垂体具有渗透激素的正常功效 。
【点评】
该研究使用特殊的三维作育情形将实验鼠的胚胎干细胞培育成能够正常渗透激素的脑垂体，关于相关疾病的病理学研究有所资助，可是由于对人类移植脑垂体需要思量的问题更多，要真正通过移植人工培育的脑垂体来治疗疾病，纵然有此可能，也还需要很长的时间 。
【参考论文】
Nature (2011) doi:10.1038/nature10637 Published online 09 November 2011
Self-formation of functional adenohypophysis in three-dimensional culture
Hidetaka Suga, Taisuke Kadoshima, Maki Minaguchi, et al.
The adenohypophysis (anterior pituitary) is a major centre for systemic hormones. At present, no efficient stem-cell culture for its generation is available, partly because of insufficient knowledge about how the pituitary primordium (Rathke’s pouch) is induced in the embryonic head ectoderm. Here we report efficient self-formation of three-dimensional adenohypophysis tissues in an aggregate culture of mouse embryonic stem (ES) cells. ES cells were stimulated to differentiate into non-neural head ectoderm and hypothalamic neuroectoderm in adjacent layers within the aggregate, and treated with hedgehog signalling. Self-organization of Rathke’s-pouch-like three-dimensional structures occurred at the interface of these two epithelia, as seen in vivo, and various endocrine cells including corticotrophs and somatotrophs were subsequently produced. The corticotrophs efficiently secreted adrenocorticotropic hormone in response to corticotrophin releasing hormone and, when grafted in vivo, these cells rescued the systemic glucocorticoid level in hypopituitary mice. Thus, functional anterior pituitary tissue self-forms in ES cell culture, recapitulating local tissue interactions.