世界生命科学前沿动态周报（六十五）

（11.7-11.13/2011）
美宝国际集团:陶国新 

　　主要内容：过表达dPGC-1延长果蝇寿命；不同微环境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；磷酸酰甘油抑制感冒病毒A的感染；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延长果蝇寿命。

1.过表达dPGC-1延长果蝇寿命
【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关键调节因子，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表明果蝇PGC-1同系物（dPGC-1）过表达足以增加线粒体活性。而且，在消化道的干细胞和祖细胞中组织特异性的过表达dPGC-1延长了果蝇寿命。过表达dPGC-1的长寿的果蝇肠道年龄相关的变化推迟了，因而促进了老龄果蝇组织的稳定性。总而言之，这些结果表明dPGC-1能够在个别组织的细胞变化和整个有机体双重水平上延缓衰老。这些发现指出一种可能性，即在像肠这样的更新很快的组织中PGC-1活性的变化可能是哺乳动物长寿的重要决定因素。

【点评】
　　这一研究结果表明PGC-1作用增强提高了果蝇线粒体的活性和作用，延长了果蝇的寿命。对于研究哺乳动物尤其是人类的衰老和抗衰老是重要的借鉴。

【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.不同微环境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微环境中的细胞循环很慢，保留标记，而另一种干细胞微环境位于腺窝底部，内住窝底柱状细胞（CBC）。CBC不同于+4细胞，二者之间的关系尚不清楚，但二者都能产生所有肠上皮细胞系。美国科学家最近发现Hopx，一种非典型同源盒蛋白，是+4细胞的新的特异性标记。表达Hopx的细胞能够产生CBC以及所有成熟的肠上皮细胞系。反之，CBC也能够产生Hopx阳性的+4细胞。这些发现表明在他们的微环境中活跃的和静止的干细胞之间存在一种双向的谱系关系。

【点评】
　　该研究意外发现分裂速度不同的两种肠干细胞能够互相产生对方，结束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能障碍是肥胖和2型糖尿病的特征。美国和瑞典的科学家建立了敲除脂肪细胞特异性核受体辅抑制物（NCoR）的老鼠模型（AKO）来研究脂肪细胞生物学、葡萄糖和胰岛素体内平衡中NCoR的功能。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减少了。AKO老鼠脂肪组织中PPAR响应基因上调，CDK5 介导的 PPAR 273号丝氨酸磷酸化减少，产生了结构上处于活化状态的PPAR。由此判断NCoR是一种适配蛋白，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 和促进PPAR 273号丝氨酸磷酸化, 因而 去除NCoR导致 脂肪生成、炎症减少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功能的阐明，有助于进一步了解肥胖和2型糖尿病的病理。对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路。

【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进行休眠和活跃周期，保证组织更新。然而，在每轮形态发生中只有一种干细胞亚群处于活跃期，意味着所有干细胞以不同反应状态共存。西班牙瑞典和美国科学家用生物钟报告器老鼠模型证明支配地位的毛囊干细胞微环境包含处于生物钟相反相但共存的细胞群，他们在分化时期已形成响应内稳态线索的倾向。核心的生物钟蛋白Bmal1以振荡方式调节干细胞调控基因的表达，以产生先天活化倾向大小不同的细胞群。通过去除Bmal或Per1/2破坏该蛋白的平衡，分别导致休眠干细胞的持续积累或消除。干细胞节律失调也会导致表皮提前衰老和鳞状癌的减少。他门的结果表明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发生的诱因。

【点评】
　　该研究结果意味着表皮干细胞的活化受到生物钟的控制，生物节律的破坏导致表皮干细胞再生能力受影响，组织提前衰老，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. 磷酸酰甘油抑制感冒病毒A的感染
【动态】
　　A型感冒病毒（IAV）是世界性的公共卫生问题，每年导致500,000人死亡。棕榈酰基油酰基磷酸酰基甘油（POPG）是肺部表面活性剂的次要成分，最近发现其有潜在的调节先天免疫的作用。美国科学家的最新研究证明POPG是很强的IAV抗病毒剂。在人体支气管上皮细胞培养中，POPG显著地调节IL-8的生产和IAV引起的细胞死亡。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的情况下在老鼠鼻内接种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-，以及感染5天后肺部的病毒数量。这些发现确认补充POPG 是一种潜在的治疗IAV感染的重要的新方法。

【点评】
　　该研究发现在肺部天然存在的一种脂类能够在细胞培养和动物模型中抑制感冒病毒感染、炎症反应、病毒传播和感染引起的细胞死亡。补充此类脂类有助于增强机体对感冒病毒的抵抗力。

【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分泌器官，它分泌多种激素，在身体生长发育、调节血压、女性乳汁分泌等多方面都发挥着重要作用。这是一个非常复杂的器官，如果功能受损也不易治疗。日本科学家最近在特殊的三维培养环境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，能够正常分泌激素。这表明医生也许可以用这种方法来治疗人类的相关疾病。本次研究显示，对于那些脑垂体有缺陷而相关激素水平下降的实验鼠，如果植入人工培育的脑垂体，相关激素水平会出现回升。这显示了人工培育的脑垂体具有分泌激素的正常功能。

【点评】
　　该研究利用特殊的三维培养环境将实验鼠的胚胎干细胞培育成能够正常分泌激素的脑垂体，对于相关疾病的病理学研究有所帮助，但是由于对人类移植脑垂体需要考虑的问题更多，要真正通过移植人工培育的脑垂体来治疗疾病，即使有此可能，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.