世界生命科學(xué)前沿動(dòng)態(tài)周報(bào)（六十）

（10.3-10.9/2011）
美寶國際集團(tuán):陶國新 

主要內(nèi)容：在多種成體干細(xì)胞和祖細(xì)胞中發(fā)現(xiàn)Sox2轉(zhuǎn)錄因子；內(nèi)源性化合物幫助老鼠逆轉(zhuǎn)糖尿病；飽和脂肪酸與不飽和脂肪酸對(duì)肥胖和糖尿病的不同影響；抗感染的新機(jī)制；抗癌藥物可能用于治療血吸蟲??；不經(jīng)過干細(xì)胞和祖細(xì)胞的細(xì)胞類型直接轉(zhuǎn)變。

焦點(diǎn)動(dòng)態(tài)：在多種成體干細(xì)胞和祖細(xì)胞中發(fā)現(xiàn)Sox2轉(zhuǎn)錄因子。

1. 在多種成體干細(xì)胞和祖細(xì)胞中發(fā)現(xiàn)Sox2轉(zhuǎn)錄因子
【動(dòng)態(tài)】
轉(zhuǎn)錄因子Sox2維持早期胚胎細(xì)胞的多能性并調(diào)節(jié)胚胎發(fā)育期數(shù)種上皮的形成。在成體組織中Sox2是否繼續(xù)起作用還不太清楚。美國科學(xué)家的最新研究表明在以前未知其表達(dá)的幾種成體的上皮組織細(xì)胞中發(fā)現(xiàn)Sox2的表達(dá)，包括胃、子宮頸、肛門、睪丸和多種腺體。遺傳譜系追蹤和移植實(shí)驗(yàn)證明表達(dá)Sox2的細(xì)胞在其組織中不斷的繁殖成熟細(xì)胞，記錄了其自我更新和分化的潛能。與這些發(fā)現(xiàn)一致，在老鼠中去除Sox2的細(xì)胞導(dǎo)致上皮組織體內(nèi)平衡的破壞和細(xì)胞死亡。發(fā)育命運(yùn)圖顯示Sox2陽性的成體細(xì)胞來源于胚胎Sox2陽性的組織前體。因此，該研究結(jié)果在多種成體內(nèi)胚層和外胚層干細(xì)胞駐地發(fā)現(xiàn)Sox2的表達(dá)，而這對(duì)于正常的組織再生和存活非常關(guān)鍵。

【點(diǎn)評(píng)】
該研究在成體干細(xì)胞中發(fā)現(xiàn)了在胚胎時(shí)期起重要作用的轉(zhuǎn)錄因子，表明人體再生的潛能一直伴隨人的生長(zhǎng)。

【參考論文】
Cell Stem Cell, October, 2011 DOI: 10.1016/j.stem.2011.09.001 
Sox2 Adult Stem and Progenitor Cells Are Important for Tissue Regeneration and Survival of Mice
Katrin Arnold, Abby Sarkar, Mary Anna Yram, et al.
The transcription factor Sox2 maintains the pluripotency of early embryonic cells and regulates the formation of several epithelia during fetal development. Whether Sox2 continues to play a role in adult tissues remains largely unknown. We show here that Sox2 marks adult cells in several epithelial tissues where its expression has not previously been characterized, including the stomach, cervix, anus, testes, lens, and multiple glands. Genetic lineage tracing and transplantation experiments demonstrate that Sox2-expressing cells continuously give rise to mature cell types within these tissues, documenting their self-renewal and differentiation potentials. Consistent with these findings, ablation of Sox2(+) cells in mice results in a disruption of epithelial tissue homeostasis and lethality. Developmental fate mapping reveals that Sox2(+) adult stem cells originate from fetal Sox2(+) tissue progenitors. Thus, our results identify Sox2 expression in numerous adult endodermal and ectodermal stem cell compartments, which are critical for normal tissue regeneration and survival.

2. 內(nèi)源性化合物幫助老鼠逆轉(zhuǎn)糖尿病
【動(dòng)態(tài)】
可能是因?yàn)楦呖防锏娘嬍硥旱沽宋覀冏赃m應(yīng)的代謝途徑，現(xiàn)代生活方式下II 型糖尿病流行開來。其中一種代謝途徑是受哺乳動(dòng)物NAD+生物合成限速酶煙酰胺磷酸核糖基轉(zhuǎn)移酶（NAMPT）以及NAD+依賴的蛋白脫乙酰基酶SIRT1調(diào)控。美國科學(xué)家最近研究顯示在代謝器官中NAMPT調(diào)控的NAD+生物合成被高脂飲食嚴(yán)重?fù)p害。出乎意料的是，煙酰胺單核苷酸（NMN），一種NAMPT的反應(yīng)產(chǎn)物和NAD+的關(guān)鍵中間體，通過恢復(fù)高脂飲食誘導(dǎo)的II型糖尿病老鼠的NAD+水平減輕了葡萄糖耐受不良。NMN也提高了肝對(duì)胰島素的敏感性并恢復(fù)了與氧化壓力、炎癥反應(yīng)以及生物鐘有關(guān)的基因表達(dá)，部分原因是激活SIRT1。而且，在衰老時(shí)，多個(gè)器官都發(fā)生明顯的NAD+ 和 NAMPT水平下降，在衰老引起的II型糖尿病老鼠中NMN能夠改善葡萄糖耐受不良和脂類構(gòu)成。這些發(fā)現(xiàn)使得有可能對(duì)飲食和衰老導(dǎo)致的II型糖尿病進(jìn)行營養(yǎng)藥干預(yù)治療。

【點(diǎn)評(píng)】
這些結(jié)果表明營養(yǎng)干預(yù)對(duì)于代謝疾病是可能起作用的。

【參考論文】
Cell Metabolism, 5 October 2011; 14(4) pp. 528 - 536 DOI:10.1016/j.cmet.2011.08.014
Nicotinamide mononucleotide, a key NAD intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice
Jun Yoshino, Kathryn F. Mills, Myeong Jin Yoon, Shin-ichiro Imai.
Highlights
NAMPT-mediated NAD+ biosynthesis is compromised in metabolic organs by HFD
NMN ameliorates defects in NAD+ biosynthesis and glucose metabolism in T2D mice
NMN enhances hepatic insulin sensitivity by reversing gene expression caused by HFD
NMN also ameliorates defects in glucose and lipid metabolism in age-induced T2D mice
Summary
Type 2 diabetes (T2D) has become epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD+ biosynthesis, and the NAD+-dependent protein deacetylase SIRT1. Here, we show that NAMPT-mediated NAD+ biosynthesis is severely compromised in metabolic organs by high-fat diet (HFD). Strikingly, nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a key NAD+ intermediate, ameliorates glucose intolerance by restoring NAD+ levels in HFD-induced T2D mice. NMN also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD+ and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide critical insights into a potential nutriceutical intervention against diet- and age-induced T2D.

3. 飽和脂肪酸與不飽和脂肪酸對(duì)肥胖和糖尿病的不同影響
【動(dòng)態(tài)】  
飽和脂肪酸對(duì)健康有不良作用，比不飽和脂肪酸更可能引起胰島素抗性，某些不飽和脂肪酸發(fā)揮保護(hù)性的有益作用。飽和脂肪酸，而非不飽和脂肪酸，激活已知在人和老鼠與肥胖和胰島素抗性有關(guān)的JNK激酶。但是如何區(qū)分飽和脂肪酸和不飽和脂肪酸還不清楚。瑞士和美國的科學(xué)家最近證明飽和脂肪酸通過激活c-Src來激活JNK激酶和抑制胰島素信號(hào)。飽和脂肪酸改變了c-Src的膜分布，使其打入細(xì)胞內(nèi)膜，在那里被激活。相反的，已知對(duì)葡萄糖代謝有有益作用的不飽和脂肪酸依靠自身豆蔻?；乐筩-Src的膜分配和激活，阻止JNK激活。消費(fèi)致糖尿病的高脂飲食引起c-Src 在鼠科脂肪細(xì)胞不溶于洗滌劑的膜區(qū)域分配和激活。

【點(diǎn)評(píng)】
該研究揭示了飽和脂肪酸和不飽和脂肪酸對(duì)肥胖和糖尿病的不同影響的機(jī)理，為改善飲食結(jié)構(gòu)提供了科學(xué)依據(jù)。

【參考論文】
Cell, 2011; 147 (1): 173-184 DOI: 10.1016/j.cell.2011.08.034  
Saturated Fatty Acids Induce c-Src Clustering within Membrane Subdomains, Leading to JNK Activation
Ryan G. Holzer, Eek-Joong Park, Ning Li, Helen Tran, et al.
Highlights
c-Src is necessary for JNK activation by saturated free fatty acids
Saturated fatty acids activate c-Src and alter its membrane distribution
Adipocytes of obese mice exhibit altered c-Src distribution and activation
Unsaturated fatty acids prevent altered c-Src distribution and JNK activation
Summary
Saturated fatty acids (FA) exert adverse health effects and are more likely to cause insulin resistance and type 2 diabetes than unsaturated FA, some of which exert protective and beneficial effects. Saturated FA, but not unsaturated FA, activate Jun N-terminal kinase (JNK), which has been linked to obesity and insulin resistance in mice and humans. However, it is unknown how saturated and unsaturated FA are discriminated. We now demonstrate that saturated FA activate JNK and inhibit insulin signaling through c-Src activation. FA alter the membrane distribution of c-Src, causing it to partition into intracellular membrane subdomains, where it likely becomes activated. Conversely, unsaturated FA with known beneficial effects on glucose metabolism prevent c-Src membrane partitioning and activation, which are dependent on its myristoylation, and block JNK activation. Consumption of a diabetogenic high-fat diet causes the partitioning and activation of c-Src within detergent insoluble membrane subdomains of murine adipocytes.

4. 抗感染的新機(jī)制
【動(dòng)態(tài)】
在病原體侵入位置存在免疫記憶是免疫保護(hù)的前提。然而，保證在外圍界面有免疫力的機(jī)制還不清楚。一個(gè)國際合作研究最近證明，在與活化的CD8αβ+ T細(xì)胞上CD8αα相互作用的樹突細(xì)胞上誘導(dǎo)的非傳統(tǒng)的主要組織相容性復(fù)合物MHC I 族分子胸腺白血病抗原（TL），調(diào)節(jié)依賴親和力的記憶前體細(xì)胞的選擇。而且，上皮細(xì)胞上TL的組成性表達(dá)導(dǎo)致連續(xù)選擇成熟的CD8αβ+ 記憶T細(xì)胞。對(duì)于在腸粘膜產(chǎn)生CD8αβ+ 記憶T細(xì)胞和積累抗原高度敏感的CD8αβ+ 記憶T細(xì)胞形成在病原體最大的入口的第一道防線，TL和CD8αα驅(qū)動(dòng)的記憶過程是必須的。

【點(diǎn)評(píng)】
該機(jī)理的闡明為開發(fā)新的疫苗提供了方向。

【參考論文】
Nature Immunology, 2011; DOI: 10.1038/ni.2106
Mucosal memory CD8 T cells are selected in the periphery by an MHC class I molecule
Yujun Huang, Yunji Park, Yiran Wang-Zhu, et al. 
The presence of immune memory at pathogen-entry sites is a prerequisite for protection. Nevertheless, the mechanisms that warrant immunity at peripheral interfaces are not understood. Here we show that the nonclassical major histocompatibility complex (MHC) class I molecule thymus leukemia antigen (TL), induced on dendritic cells interacting with CD8αα on activated CD8αβ+ T cells, mediated affinity-based selection of memory precursor cells. Furthermore, constitutive expression of TL on epithelial cells led to continued selection of mature CD8αβ+ memory T cells. The memory process driven by TL and CD8αα was essential for the generation of CD8αβ+ memory T cells in the intestine and the accumulation of highly antigen-sensitive CD8αβ+ memory T cells that form the first line of defense at the largest entry port for pathogens.

5. 抗癌藥物可能用于治療血吸蟲病
【動(dòng)態(tài)】
血吸蟲病是寄生蟲引起的傳染病。澳大利亞的科學(xué)家報(bào)道了在日本血吸蟲中識(shí)別和鑒定Bcl-2調(diào)節(jié)的凋亡途徑?；蚪M學(xué)、生物化學(xué)和基于細(xì)胞的機(jī)理研究為三重途徑理論提供了證據(jù)，類似于人體中受促存活的Bcl-2樣分子抑制的只包含BH3的蛋白，以及促進(jìn)線粒體外膜穿透的Bax-Bak樣蛋白。Bcl-2蛋白已被成功用于開發(fā)BH3模擬物藥物特別是癌癥治療藥，而該研究發(fā)現(xiàn)一種血吸蟲促存活蛋白sjA與已知的BH3模擬物ABT-737結(jié)合，為BH3模擬物類抗癌藥物用于治療血吸蟲病提供了理論基礎(chǔ)。

【點(diǎn)評(píng)】
血吸蟲細(xì)胞凋亡途徑的研究發(fā)現(xiàn)了能與已知BH3模擬物類抗癌藥相結(jié)合的促存活蛋白，為開發(fā)此類血吸蟲病治療藥物提供了理論依據(jù)。

【參考論文】
PNAS, 2011; 108 (17): 6999 DOI: 10.1073/pnas.1100652108
From the Cover: Discovery and molecular characterization of a Bcl-2-regulated cell death pathway in schistosomes
E. F. Lee, O. B. Clarke, M. Evangelista, et al.
Schistosomiasis is an infectious disease caused by parasites of the phylum platyhelminthe. Here, we describe the identification and characterization of a Bcl-2–regulated apoptosis pathway in Schistosoma japonicum and S. mansoni. Genomic, biochemical, and cell-based mechanistic studies provide evidence for a tripartite pathway, similar to that in humans including BH3-only proteins that are inhibited by prosurvival Bcl-2–like molecules, and Bax/Bak-like proteins that facilitate mitochondrial outer-membrane permeabilization. Because Bcl-2 proteins have been successfully targeted with “BH3 mimetic” drugs, particularly in the treatment of cancer, we investigated whether schistosome apoptosis pathways could provide targets for future antischistosomal drug discovery efforts. Accordingly, we showed that a schistosome prosurvival protein, sjA, binds ABT-737, a well-characterized BH3 mimetic. A crystal structure of sjA bound to a BH3 peptide provides direct evidence for the feasibility of developing BH3 mimetics to target Bcl-2 prosurvival proteins in schistosomes, suggesting an alternative application for this class of drugs beyond cancer treatment.

6. 不經(jīng)過干細(xì)胞和祖細(xì)胞的細(xì)胞類型直接轉(zhuǎn)變
【動(dòng)態(tài)】
早前的工作表明未成熟的B細(xì)胞經(jīng)常會(huì)被轉(zhuǎn)錄因子CCAAT/增強(qiáng)子結(jié)合蛋白α轉(zhuǎn)變?yōu)榫奘杉?xì)胞。西班牙和瑞典的科學(xué)家利用這一體系系統(tǒng)分析了在轉(zhuǎn)分化細(xì)胞中是否暫時(shí)性的重新激活了在祖細(xì)胞中被限制的基因甚至逆分化。轉(zhuǎn)分化細(xì)胞的轉(zhuǎn)錄譜分析表明大部分基因連續(xù)上調(diào)或下調(diào)，在5天內(nèi)表現(xiàn)出巨噬細(xì)胞的表型。另外，實(shí)驗(yàn)還觀察到一小組未成熟骨髓標(biāo)志物的短暫重新激活，以及低水平的祖細(xì)胞標(biāo)記Kit和FMS樣的酪氨酸激酶3和少量非本細(xì)胞系的基因。而重要的是，沒有觀察到鑒別造血干細(xì)胞和祖細(xì)胞的包括c-Kit和FMS樣的酪氨酸激酶3的膜標(biāo)志物的重新表達(dá)，即使CCAAT/增強(qiáng)子結(jié)合蛋白α是在適宜造血干細(xì)胞和祖細(xì)胞生長(zhǎng)的條件下培養(yǎng)的未成熟B細(xì)胞中被激活的或該轉(zhuǎn)錄因子是以時(shí)間限制性的方式激活的。總體看來，該研究的發(fā)現(xiàn)符合以下觀念：從未成熟B細(xì)胞到巨噬細(xì)胞的轉(zhuǎn)變基本是直接的，不涉及明顯的逆分化。

【點(diǎn)評(píng)】
該研究表明存在以下可能：從一種體細(xì)胞不經(jīng)過所謂逆分化為干細(xì)胞和祖細(xì)胞就能夠直接轉(zhuǎn)變?yōu)榱硪环N體細(xì)胞。

【參考論文】
Proc Natl Acad Sci, 108: 17016- 17021 DOI: 10.1073/pnas.1112169108
CCAAT/enhancer binding protein α (C/EBP α)-induced transdifferentiation of pre-B cells into macrophages involves no overt retrodifferentiation
Di Tullio, A. et al.
Earlier work has shown that pre-B cells can be converted into macrophages by the transcription factor CCAAT/enhancer binding protein α at very high frequencies. Using this system, we performed a systematic analysis of whether during transdifferentiation the cells transiently reactivate progenitor-restricted genes or even retrodifferentiate. A transcriptome analysis of transdifferentiating cells showed that most genes are up- or down-regulated continuously, acquiring a macrophage phenotype within 5 d. In addition, we observed the transient reactivation of a subset of immature myeloid markers, as well as low levels of the progenitor markers Kit and FMS-like tyrosine kinase 3 and a few lineage-inappropriate genes. Importantly, however, we were unable to observe the reexpression of cell-surface marker combinations that characterize hematopoietic stem and progenitor cells, including c-Kit and FMS-like tyrosine kinase 3, even when CAAT/enhancer binding protein α was activated in pre-B cells under culture conditions that favor growth of hematopoietic stem and progenitor cells or when the transcription factor was activated in a time-limited fashion. Together, our findings are consistent with the notion that the conversion from pre-B cells to macrophages is mostly direct and does not involve overt retrodifferentiation.