世界生命科學(xué)前沿動(dòng)態(tài)周報(bào)（六十五）

（11.7-11.13/2011）
美寶國際集團(tuán):陶國新 

　　主要內(nèi)容：過表達(dá)dPGC-1延長果蠅壽命；不同微環(huán)境中的腸干細(xì)胞之間的相互轉(zhuǎn)換；脂肪細(xì)胞去除NCoR降低了PPARγ磷酸化增強(qiáng)了 PPARγ 的作用和胰島素敏感性；生物鐘造成表皮干細(xì)胞的異質(zhì)性；磷酸酰甘油抑制感冒病毒A的感染；用實(shí)驗(yàn)鼠的胚胎干細(xì)胞培育出腦垂體。

　　焦點(diǎn)動(dòng)態(tài)：過表達(dá)dPGC-1延長果蠅壽命。

1.過表達(dá)dPGC-1延長果蠅壽命
【動(dòng)態(tài)】
　　哺乳動(dòng)物的PGC-1轉(zhuǎn)錄共激活物是其能量代謝，包括線粒體生物合成和呼吸作用的關(guān)鍵調(diào)節(jié)因子，這已體現(xiàn)在在包括神經(jīng)退行性病變和心肌病變等許多病變中。而美國科學(xué)家最新的研究表明果蠅PGC-1同系物（dPGC-1）過表達(dá)足以增加線粒體活性。而且，在消化道的干細(xì)胞和祖細(xì)胞中組織特異性的過表達(dá)dPGC-1延長了果蠅壽命。過表達(dá)dPGC-1的長壽的果蠅腸道年齡相關(guān)的變化推遲了，因而促進(jìn)了老齡果蠅組織的穩(wěn)定性?？偠灾?，這些結(jié)果表明dPGC-1能夠在個(gè)別組織的細(xì)胞變化和整個(gè)有機(jī)體雙重水平上延緩衰老。這些發(fā)現(xiàn)指出一種可能性，即在像腸這樣的更新很快的組織中PGC-1活性的變化可能是哺乳動(dòng)物長壽的重要決定因素。

【點(diǎn)評(píng)】
　　這一研究結(jié)果表明PGC-1作用增強(qiáng)提高了果蠅線粒體的活性和作用，延長了果蠅的壽命。對(duì)于研究哺乳動(dòng)物尤其是人類的衰老和抗衰老是重要的借鑒。

【參考論文】
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.不同微環(huán)境中的腸干細(xì)胞之間的相互轉(zhuǎn)換
【動(dòng)態(tài)】
　　腸上皮干細(xì)胞的識(shí)別和定位一直是個(gè)需要實(shí)質(zhì)研究的事情。+4微環(huán)境中的細(xì)胞循環(huán)很慢，保留標(biāo)記，而另一種干細(xì)胞微環(huán)境位于腺窩底部，內(nèi)住窩底柱狀細(xì)胞（CBC）。CBC不同于+4細(xì)胞，二者之間的關(guān)系尚不清楚，但二者都能產(chǎn)生所有腸上皮細(xì)胞系。美國科學(xué)家最近發(fā)現(xiàn)Hopx，一種非典型同源盒蛋白，是+4細(xì)胞的新的特異性標(biāo)記。表達(dá)Hopx的細(xì)胞能夠產(chǎn)生CBC以及所有成熟的腸上皮細(xì)胞系。反之，CBC也能夠產(chǎn)生Hopx陽性的+4細(xì)胞。這些發(fā)現(xiàn)表明在他們的微環(huán)境中活躍的和靜止的干細(xì)胞之間存在一種雙向的譜系關(guān)系。

【點(diǎn)評(píng)】
　　該研究意外發(fā)現(xiàn)分裂速度不同的兩種腸干細(xì)胞能夠互相產(chǎn)生對(duì)方，結(jié)束了誰是真正的腸干細(xì)胞的爭(zhēng)論。

【參考論文】
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.脂肪細(xì)胞去除NCoR降低了 PPARγ 磷酸化增強(qiáng)了 PPARγ 的作用和胰島素敏感性
【動(dòng)態(tài)】
　　胰島素抗性、組織發(fā)炎和脂肪組織功能障礙是肥胖和2型糖尿病的特征。美國和瑞典的科學(xué)家建立了敲除脂肪細(xì)胞特異性核受體輔抑制物（NCoR）的老鼠模型（AKO）來研究脂肪細(xì)胞生物學(xué)、葡萄糖和胰島素體內(nèi)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，肝臟、肌肉和脂肪中胰島素敏感性增強(qiáng)了。脂肪組織巨噬細(xì)胞浸潤和炎癥減少了。AKO老鼠脂肪組織中PPAR響應(yīng)基因上調(diào)，CDK5 介導(dǎo)的 PPAR 273號(hào)絲氨酸磷酸化減少，產(chǎn)生了結(jié)構(gòu)上處于活化狀態(tài)的PPAR。由此判斷NCoR是一種適配蛋白，作用是增強(qiáng)CDK5聯(lián)系和磷酸化PPAR的能力。脂肪細(xì)胞NCoR
的主導(dǎo)作用是反抑制PPAR 和促進(jìn)PPAR 273號(hào)絲氨酸磷酸化, 因而 去除NCoR導(dǎo)致 脂肪生成、炎癥減少和全身胰島素敏感性增強(qiáng)，模擬了TZD藥物治療的狀態(tài)。

【點(diǎn)評(píng)】
　　NCoR功能的闡明，有助于進(jìn)一步了解肥胖和2型糖尿病的病理。對(duì)于研發(fā)通過增強(qiáng)胰島素敏感性手段的治療2型糖尿病提供了新的思路。

【參考論文】
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.生物鐘造成表皮干細(xì)胞的異質(zhì)性
【動(dòng)態(tài)】
　　鼠類表皮干細(xì)胞交替進(jìn)行休眠和活躍周期，保證組織更新。然而，在每輪形態(tài)發(fā)生中只有一種干細(xì)胞亞群處于活躍期，意味著所有干細(xì)胞以不同反應(yīng)狀態(tài)共存。西班牙瑞典和美國科學(xué)家用生物鐘報(bào)告器老鼠模型證明支配地位的毛囊干細(xì)胞微環(huán)境包含處于生物鐘相反相但共存的細(xì)胞群，他們?cè)诜只瘯r(shí)期已形成響應(yīng)內(nèi)穩(wěn)態(tài)線索的傾向。核心的生物鐘蛋白Bmal1以振蕩方式調(diào)節(jié)干細(xì)胞調(diào)控基因的表達(dá)，以產(chǎn)生先天活化傾向大小不同的細(xì)胞群。通過去除Bmal或Per1/2破壞該蛋白的平衡，分別導(dǎo)致休眠干細(xì)胞的持續(xù)積累或消除。干細(xì)胞節(jié)律失調(diào)也會(huì)導(dǎo)致表皮提前衰老和鱗狀癌的減少。他門的結(jié)果表明生物鐘微調(diào)表皮干細(xì)胞的一時(shí)行為，該擾動(dòng)影響內(nèi)平衡和腫瘤發(fā)生的誘因。

【點(diǎn)評(píng)】
　　該研究結(jié)果意味著表皮干細(xì)胞的活化受到生物鐘的控制，生物節(jié)律的破壞導(dǎo)致表皮干細(xì)胞再生能力受影響，組織提前衰老，更易誘發(fā)皮膚癌。

【參考論文】
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
【動(dòng)態(tài)】
　　A型感冒病毒（IAV）是世界性的公共衛(wèi)生問題，每年導(dǎo)致500,000人死亡。棕櫚?；王；姿狨；视停≒OPG）是肺部表面活性劑的次要成分，最近發(fā)現(xiàn)其有潛在的調(diào)節(jié)先天免疫的作用。美國科學(xué)家的最新研究證明POPG是很強(qiáng)的IAV抗病毒劑。在人體支氣管上皮細(xì)胞培養(yǎng)中，POPG顯著地調(diào)節(jié)IL-8的生產(chǎn)和IAV引起的細(xì)胞死亡。這種脂類還抑制病毒對(duì)細(xì)胞膜的粘附及隨后在MDCK細(xì)胞中的復(fù)制。H1N1-PR8-IAV和H3N2-IAV兩種病毒株與POPG有很高的親和力但對(duì)結(jié)構(gòu)類似的脂類   磷脂酰膽堿親和力卻很低。在有POPG的情況下在老鼠鼻內(nèi)接種H1N1-PR8-IAV顯著抑制 了炎癥細(xì)胞的浸潤和支氣管肺泡灌洗誘導(dǎo)的IFN-，以及感染5天后肺部的病毒數(shù)量。這些發(fā)現(xiàn)確認(rèn)補(bǔ)充POPG 是一種潛在的治療IAV感染的重要的新方法。

【點(diǎn)評(píng)】
　　該研究發(fā)現(xiàn)在肺部天然存在的一種脂類能夠在細(xì)胞培養(yǎng)和動(dòng)物模型中抑制感冒病毒感染、炎癥反應(yīng)、病毒傳播和感染引起的細(xì)胞死亡。補(bǔ)充此類脂類有助于增強(qiáng)機(jī)體對(duì)感冒病毒的抵抗力。

【參考論文】
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.用實(shí)驗(yàn)鼠的胚胎干細(xì)胞培育出腦垂體
【動(dòng)態(tài)】
　　腦垂體是位于大腦下部的一個(gè)內(nèi)分泌器官，它分泌多種激素，在身體生長發(fā)育、調(diào)節(jié)血壓、女性乳汁分泌等多方面都發(fā)揮著重要作用。這是一個(gè)非常復(fù)雜的器官，如果功能受損也不易治療。日本科學(xué)家最近在特殊的三維培養(yǎng)環(huán)境中用實(shí)驗(yàn)鼠的胚胎干細(xì)胞培育出腦垂體，并且培育出的腦垂體在移植給原本腦垂體有缺陷的實(shí)驗(yàn)鼠后，能夠正常分泌激素。這表明醫(yī)生也許可以用這種方法來治療人類的相關(guān)疾病。本次研究顯示，對(duì)于那些腦垂體有缺陷而相關(guān)激素水平下降的實(shí)驗(yàn)鼠，如果植入人工培育的腦垂體，相關(guān)激素水平會(huì)出現(xiàn)回升。這顯示了人工培育的腦垂體具有分泌激素的正常功能。

【點(diǎn)評(píng)】
　　該研究利用特殊的三維培養(yǎng)環(huán)境將實(shí)驗(yàn)鼠的胚胎干細(xì)胞培育成能夠正常分泌激素的腦垂體，對(duì)于相關(guān)疾病的病理學(xué)研究有所幫助，但是由于對(duì)人類移植腦垂體需要考慮的問題更多，要真正通過移植人工培育的腦垂體來治療疾病，即使有此可能，也還需要很長的時(shí)間。

【參考論文】
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.