世界生命科学前沿动态周报（六十）

（10.3-10.9/2011）
美宝国际集团:陶国新 

主要内容：在多种成体干细胞和祖细胞中发现Sox2转录因子；内源性化合物帮助老鼠逆转糖尿病；饱和脂肪酸与不饱和脂肪酸对肥胖和糖尿病的不同影响；抗感染的新机制；抗癌药物可能用于治疗血吸虫病；不经过干细胞和祖细胞的细胞类型直接转变。

焦点动态：在多种成体干细胞和祖细胞中发现Sox2转录因子。

1. 在多种成体干细胞和祖细胞中发现Sox2转录因子
【动态】
转录因子Sox2维持早期胚胎细胞的多能性并调节胚胎发育期数种上皮的形成。在成体组织中Sox2是否继续起作用还不太清楚。美国科学家的最新研究表明在以前未知其表达的几种成体的上皮组织细胞中发现Sox2的表达，包括胃、子宫颈、肛门、睾丸和多种腺体。遗传谱系追踪和移植实验证明表达Sox2的细胞在其组织中不断的繁殖成熟细胞，记录了其自我更新和分化的潜能。与这些发现一致，在老鼠中去除Sox2的细胞导致上皮组织体内平衡的破坏和细胞死亡。发育命运图显示Sox2阳性的成体细胞来源于胚胎Sox2阳性的组织前体。因此，该研究结果在多种成体内胚层和外胚层干细胞驻地发现Sox2的表达，而这对于正常的组织再生和存活非常关键。

【点评】
该研究在成体干细胞中发现了在胚胎时期起重要作用的转录因子，表明人体再生的潜能一直伴随人的生长。

【参考论文】
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. 内源性化合物帮助老鼠逆转糖尿病
【动态】
可能是因为高卡路里的饮食压倒了我们自适应的代谢途径，现代生活方式下II 型糖尿病流行开来。其中一种代谢途径是受哺乳动物NAD+生物合成限速酶烟酰胺磷酸核糖基转移酶（NAMPT）以及NAD+依赖的蛋白脱乙酰基酶SIRT1调控。美国科学家最近研究显示在代谢器官中NAMPT调控的NAD+生物合成被高脂饮食严重损害。出乎意料的是，烟酰胺单核苷酸（NMN），一种NAMPT的反应产物和NAD+的关键中间体，通过恢复高脂饮食诱导的II型糖尿病老鼠的NAD+水平减轻了葡萄糖耐受不良。NMN也提高了肝对胰岛素的敏感性并恢复了与氧化压力、炎症反应以及生物钟有关的基因表达，部分原因是激活SIRT1。而且，在衰老时，多个器官都发生明显的NAD+ 和 NAMPT水平下降，在衰老引起的II型糖尿病老鼠中NMN能够改善葡萄糖耐受不良和脂类构成。这些发现使得有可能对饮食和衰老导致的II型糖尿病进行营养药干预治疗。

【点评】
这些结果表明营养干预对于代谢疾病是可能起作用的。

【参考论文】
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. 饱和脂肪酸与不饱和脂肪酸对肥胖和糖尿病的不同影响
【动态】  
饱和脂肪酸对健康有不良作用，比不饱和脂肪酸更可能引起胰岛素抗性，某些不饱和脂肪酸发挥保护性的有益作用。饱和脂肪酸，而非不饱和脂肪酸，激活已知在人和老鼠与肥胖和胰岛素抗性有关的JNK激酶。但是如何区分饱和脂肪酸和不饱和脂肪酸还不清楚。瑞士和美国的科学家最近证明饱和脂肪酸通过激活c-Src来激活JNK激酶和抑制胰岛素信号。饱和脂肪酸改变了c-Src的膜分布，使其打入细胞内膜，在那里被激活。相反的，已知对葡萄糖代谢有有益作用的不饱和脂肪酸依靠自身豆蔻酰化防止c-Src的膜分配和激活，阻止JNK激活。消费致糖尿病的高脂饮食引起c-Src 在鼠科脂肪细胞不溶于洗涤剂的膜区域分配和激活。

【点评】
该研究揭示了饱和脂肪酸和不饱和脂肪酸对肥胖和糖尿病的不同影响的机理，为改善饮食结构提供了科学依据。

【参考论文】
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. 抗感染的新机制
【动态】
在病原体侵入位置存在免疫记忆是免疫保护的前提。然而，保证在外围界面有免疫力的机制还不清楚。一个国际合作研究最近证明，在与活化的CD8αβ+ T细胞上CD8αα相互作用的树突细胞上诱导的非传统的主要组织相容性复合物MHC I 族分子胸腺白血病抗原（TL），调节依赖亲和力的记忆前体细胞的选择。而且，上皮细胞上TL的组成性表达导致连续选择成熟的CD8αβ+ 记忆T细胞。对于在肠粘膜产生CD8αβ+ 记忆T细胞和积累抗原高度敏感的CD8αβ+ 记忆T细胞形成在病原体最大的入口的第一道防线，TL和CD8αα驱动的记忆过程是必须的。

【点评】
该机理的阐明为开发新的疫苗提供了方向。

【参考论文】
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. 抗癌药物可能用于治疗血吸虫病
【动态】
血吸虫病是寄生虫引起的传染病。澳大利亚的科学家报道了在日本血吸虫中识别和鉴定Bcl-2调节的凋亡途径。基因组学、生物化学和基于细胞的机理研究为三重途径理论提供了证据，类似于人体中受促存活的Bcl-2样分子抑制的只包含BH3的蛋白，以及促进线粒体外膜穿透的Bax-Bak样蛋白。Bcl-2蛋白已被成功用于开发BH3模拟物药物特别是癌症治疗药，而该研究发现一种血吸虫促存活蛋白sjA与已知的BH3模拟物ABT-737结合，为BH3模拟物类抗癌药物用于治疗血吸虫病提供了理论基础。

【点评】
血吸虫细胞凋亡途径的研究发现了能与已知BH3模拟物类抗癌药相结合的促存活蛋白，为开发此类血吸虫病治疗药物提供了理论依据。

【参考论文】
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. 不经过干细胞和祖细胞的细胞类型直接转变
【动态】
早前的工作表明未成熟的B细胞经常会被转录因子CCAAT/增强子结合蛋白α转变为巨噬细胞。西班牙和瑞典的科学家利用这一体系系统分析了在转分化细胞中是否暂时性的重新激活了在祖细胞中被限制的基因甚至逆分化。转分化细胞的转录谱分析表明大部分基因连续上调或下调，在5天内表现出巨噬细胞的表型。另外，实验还观察到一小组未成熟骨髓标志物的短暂重新激活，以及低水平的祖细胞标记Kit和FMS样的酪氨酸激酶3和少量非本细胞系的基因。而重要的是，没有观察到鉴别造血干细胞和祖细胞的包括c-Kit和FMS样的酪氨酸激酶3的膜标志物的重新表达，即使CCAAT/增强子结合蛋白α是在适宜造血干细胞和祖细胞生长的条件下培养的未成熟B细胞中被激活的或该转录因子是以时间限制性的方式激活的。总体看来，该研究的发现符合以下观念：从未成熟B细胞到巨噬细胞的转变基本是直接的，不涉及明显的逆分化。

【点评】
该研究表明存在以下可能：从一种体细胞不经过所谓逆分化为干细胞和祖细胞就能够直接转变为另一种体细胞。

【参考论文】
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.