企业邮箱
天下生命科学前沿动态周报（四十五）
（4.25-5.1/2011）
一竞技国际集团:陶国新
主要内容：正常细胞和肿瘤细胞能够自觉转变为干细胞样状态 ；发明能够将特定细胞转变为生产胰岛素的细胞的机制 ；通过激活成熟神经元中的BMP/Smad1信号通路再生受伤脊椎中的轴突神经 ；线粒体作治疗癌症的靶点 ；小分子协同作用维持人体胚胎干细胞早期分解后的恒久稳固自我更新 ；判别出与肌肉修复有关的要害基因。
1. 正常细胞和肿瘤细胞能够自觉转变为干细胞样状态
【动态】
现在的干细胞生物学模子假定正常干细胞和肿瘤干细胞都是位于细胞条理结构的顶端，单向分解形成非干细胞的子女。美国MIT的科学家发明一类不切合该假设的人基底样乳腺上皮细胞能够自觉逆转酿成干细胞样细胞。并且，致癌性转化增强这一自觉转变，因而在体内外由非干细胞的癌细胞能够爆发肿瘤干细胞样细胞。他们进一步研究批注正常起始细胞的分解状态很洪流平上决议着它转变后的行为。这些发明说明正常细胞和肿瘤干细胞样细胞能够从分解更充分的细胞全新爆发，乳腺干细胞生物学的条理模子应该包括干细胞与非干细胞的双向互变。这一可塑性或许能促成不需操控基因而生产患者特有成体干细胞的要领，关于制订根除癌症的治疗战略也有主要意义。
【点评】
该发明说明非干细胞可以自觉转酿成干细胞，这一点在潜能再生细胞早已体现。另外，通俗肿瘤细胞也可以自觉转酿成肿瘤干细胞，这使得癌症并不是可以通过除掉肿瘤干细胞就能治愈。
【参考论文】 PNAS, 2011; DOI: 10.1073/pnas.1102454108
Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state
Christine L. Chaffer, Ines Brueckmann, Christina Scheel, et al.
Current models of stem cell biology assume that normal and neoplastic stem cells reside at the apices of hierarchies and differentiate into nonstem progeny in a unidirectional manner. Here we identify a subpopulation of basal-like human mammary epithelial cells that departs from that assumption, spontaneously dedifferentiating into stem-like cells. Moreover, oncogenic transformation enhances the spontaneous conversion, so that nonstem cancer cells give rise to cancer stem cell (CSC)-like cells in vitro and in vivo. We further show that the differentiation state of normal cells-of-origin is a strong determinant of posttransformation behavior. These findings demonstrate that normal and CSC-like cells can arise de novo from more differentiated cell types and that hierarchical models of mammary stem cell biology should encompass bidirectional interconversions between stem and nonstem compartments. The observed plasticity may allow derivation of patient-specific adult stem cells without genetic manipulation and holds important implications for therapeutic strategies to eradicate cancer.
2. 发明能够将特定细胞转变为生产胰岛素的细胞的机制
【动态】
只管作为目今糖尿病的标准疗法的胰岛素治疗能够资助患者维持血糖水平，但并不完善，许多患者依旧有很高的危害患上州并发症� ；指慈笔У纳鹊核氐摩孪赴赜�1型和2型糖尿病可能会是更彻底的解决计划。胰腺β细胞身份靠DNA甲基化介导的Arx抑制来维持。删除Dnmt1导致β 细胞重组为 α 细胞。在β细胞中Arx被抑制，而该抑制被去除会使β细胞转变为α细胞。在生长中和受伤后成熟的胰腺β细胞会复制以维持血糖的稳固。发明缺乏在细胞破碎中传送DNA甲基化模式的酶Dnmt1的β细胞转酿成了α细胞。判别出细胞系决议基因Arx, Arx在β细胞中是甲基化和被抑制的，在α细胞和缺乏Dnmt1的β细胞中是低甲基化并表达的。β细胞中Arx的甲基化位点团结了甲基团结卵白MeCP2,该卵白招募甲基化组卵白H3R2的酶PRMT6导致Arx的抑制。这批注在细胞破碎中传送DNA甲基化也包管了能够修饰和转达组卵白标记的酶机制的启用。新的研究效果展现了在细胞破碎中传送DNA甲基化是抑制α 细胞系决议基因维持β细胞身份所必需的。
【点评】
胰腺β细胞转变为α细胞的机制说明DNA甲基化等表观调控是决议细胞生命属性的主要因素，单只DNA自己并不可决议细胞的生命属性。这也为合理调理表观调控以影响细胞生命属性提供了科学依据。
【参考论文】Developmental Cell, 2011; 20 (4): 419 DOI:10.1016/j.devcel.2011.03.012
Pancreatic β Cell Identity Is Maintained by DNA Methylation-Mediated Repression of Arx
Sangeeta Dhawan, Senta Georgia, Shuen-ing Tschen, Guoping Fan, Anil Bhushan
Adult pancreatic β cells can replicate during growth and after injury to maintain glucose homeostasis. Here, we report that β cells deficient in Dnmt1, an enzyme that propagates DNA methylation patterns during cell division, were converted to α cells. We identified the lineage determination gene aristaless-related homeobox (Arx), as methylated and repressed in β cells, and hypomethylated and expressed in α cells and Dnmt1-deficient β cells. We show that the methylated region of the Arx locus in β cells was bound by methyl-binding protein MeCP2, which recruited PRMT6, an enzyme that methylates histone H3R2 resulting in repression of Arx. This suggests that propagation of DNA methylation during cell division also ensures recruitment of enzymatic machinery capable of modifying and transmitting histone marks. Our results reveal that propagation of DNA methylation during cell division is essential for repression of α cell lineage determination genes to maintain pancreatic β cell identity.
3.通过激活成熟神经元中的BMP/Smad1信号通路再生受伤脊椎中的轴突神经
【动态】
轴突生长潜力在年轻神经元中最高但随年岁增添而消逝，因而成为成体受伤后轴突再生的显著障碍。一项新研究批注在DRG神经元中Smad1依赖的骨成型卵白（BMP）逐步被调理控制轴突生长。下调该途径造成年岁相关的轴突生长潜力的下降。在成熟的DRG神经元中选择性重新激活Smad1导致脊椎损伤的老鼠模子感受神经再生。Smad1信号可以通过临床适用的最小侵入手艺运送编码BMP4的AAV载体来有用的操控。主要的是，纵然是脊椎损伤后实验AAV治疗，断了的轴突也能再生，因此很像响应的临床事务。
【点评】
这一神经再生的研究也说明DNA并非决议细胞生运气动的要害，对基因表达的调控更主要。
【参考论文】PNAS 2011, doi: 10.1073/pnas.1100426108
Regeneration of axons in injured spinal cord by activation of bone morphogenetic protein/Smad1 signaling pathway in adult neurons
Pranav Parikha, Yuhan Haoa, Mohsen Hosseinkhania.
Axon growth potential is highest in young neurons but diminishes with age, thus becoming a significant obstacle to axonal regeneration after injury in maturity. The mechanism for the decline is incompletely understood, and no effective clinical treatment is available to rekindle innate growth capability. Here, we show that Smad1-dependent bone morphogenetic protein (BMP) signaling is developmentally regulated and governs axonal growth in dorsal root ganglion (DRG) neurons. Down-regulation of the pathway contributes to the age-related decline of the axon growth potential. Reactivating Smad1 selectively in adult DRG neurons results in sensory axon regeneration in a mouse model of spinal cord injury (SCI). Smad1 signaling can be effectively manipulated by an adeno-associated virus (AAV) vector encoding BMP4 delivered by a clinically applicable and minimally invasive technique, an approach devoid of unwanted abnormalities in mechanosensation or pain perception. Importantly, transected axons are able to regenerate even when the AAV treatment is delivered after SCI, thus mimicking a clinically relevant scenario. Together, our results identify a therapeutic target to promote axonal regeneration after SCI.
4. 线粒体作治疗癌症的靶点
【动态】
有关癌细胞线粒体的一些研究指导了生长针对线粒体卵白和功效的无遗传毒性的抗癌疗法。现在已经明确的线粒体在细胞凋亡中的作用提供了肿瘤细胞自杀的新靶点。线粒体的作用是作为对细胞压力和损伤做出反应的中央转换器�？梢哉攵园┫赴械贾旅庥诘蛲龅哪切┳淅匆种破湓鲋�。由于癌细胞代谢的重组涉及到增添糖酵解，看起来通过针对HIF-1 或HIF-1基因编码的代谢酶来阻断InsP3R Ca2+的释放或响应缺氧的顺应性途径代表了一种可行的癌症治疗要领。在体外向癌细胞添加白藜芦醇后很快爆发的是细胞内数秒内即可测到的Ca2+的增多。在添加无毒的类黄酮时也视察到Ca2+的释放，看来值得找出钙活化中涉及的模子化合物白藜芦醇的作用靶点。
【点评】
针对癌细胞线粒体与正常细胞线粒体的差别举行癌症治疗的思绪是对的,可是现在这种差别的细节还不是很清晰。
【参考论文】Journal of cellular physiology. 2011 DOI 10.1002/jcp.22788
Targeting mitochondria as a therapeutic target in cancer
Wenner CE
Knowledge of re-programming in cancer cells with metabolic differences from their normal counterparts has resulted in new examination of therapeutic approaches. Several studies of the role of tumor mitochondria in cancer have led to the development of non-genotoxic therapies which target mitochondrial proteins, function. The now well-established functions of mitochondria in apoptosis provide novel targets for tumor cell suicide. Mitochondria serve as a central hub for responses to cellular stress as well as injury. The alterations in cancer cells which result in protection from apoptosis can be targeted to inhibit proliferation. Because of the reprogramming of cancer cell metabolism involving increased glycolysis, it appears that blocking InsP3R Ca2+ release or adaptive pathways in response to hypoxia by targeting HIF-1 or metabolic enzymes encoded by the HIF-1 gene represents a feasible therapeutic approach to cancer. A very early in vitro event found in tumor cells following resveratrol addition is an increase in intracellular Ca2+, measurable within seconds. Ca2+ release is also observed with non-toxic flavonoids and a goal to identify the sentinel targets of resveratrol as a model compound involved in calcium activation seems worthwhile. New findings of the relationship between autophagy and apoptosis are discussed. The contribution of ROS generated by mitochondria is also considered. New data as to how cyclophilins and VDAC are involved in mitochondrial hexokinase protection of factors that induce apoptosis are reviewed. In addition, chemotherapeutic approaches based on Aktactivated mTORC1 are described, and their relationship to the role of aerobic glycolysis in this protection.
5. 小分子协同作用维持人体胚胎干细胞早期分解后的恒久稳固自我更新
【动态】
小分子抑制剂迅速诱导人体胚胎干细胞转变为原始神经祖细胞并维持恒久自我更新。人体胚胎干细胞付与了再生医学重大希望。通凡人体胚胎干细胞的应用需要其在体外分解成期望的均一细胞群。现在的人体胚胎干细胞分解模式面临的一个主要挑战是不可有用锁定并恒久稳固扩增那些保有普遍的分解能力，更主要的是发育阶段特异性的分解倾向的原始的细胞系特异性干细胞/祖细胞群。一项新的研究报告了用小分子协同抑制糖原合成酶激酶3（GSK3）,转化生长因子β (TGF-β)，和Notch信号途径能够在特定化学条件下于一周内有用的将单层作育的人体胚胎干细胞转酿成均一的原始神经上皮细胞。这些原始神经上皮能够在白细胞抑制因子，GSK3抑制剂（CHIR99021）和TGF-β受体抑制剂（SB431542）保存的情形下稳固的自我更新 ；坚持高潜力的神经生长能力和对中脑后脑神经亚型指导性神经模式线索的反应性 ；并体现出体内的整体性。
【点评】
通过小分子抑制剂协同作用调控差别的信号途径，来抵达阻止干细胞进一步分解和维持干细胞恒久稳固扩增，关于干细胞体外作育照旧有些价值的，只是这种人为划定的情形下培育的干细胞能否施展体内正常心理条件下的干细胞功效尚有很大疑问。
【参考论文】PNAS 2011 ; doi:10.1073/pnas.1014041108
Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by small molecule inhibitors
Wenlin Li, Woong Sun, Yu Zhang, et al.
Human embryonic stem cells (hESCs) hold enormous promise for regenerative medicine. Typically, hESC-based applications would require their in vitro differentiation into a desirable homogenous cell population. A major challenge of the current hESC differentiation paradigm is the inability to effectively capture and, in the long-term, stably expand primitive lineage-specific stem/precursor cells that retain broad differentiation potential and, more importantly, developmental stage-specific differentiation propensity. Here, we report synergistic inhibition of glycogen synthase kinase 3 (GSK3), transforming growth factor β (TGF-β), and Notch signaling pathways by small molecules can efficiently convert monolayer cultured hESCs into homogenous primitive neuroepithelium within 1 wk under chemically defined condition. These primitive neuroepithelia can stably self-renew in the presence of leukemia inhibitory factor, GSK3 inhibitor (CHIR99021), and TGF-β receptor inhibitor (SB431542); retain high neurogenic potential and responsiveness to instructive neural patterning cues toward midbrain and hindbrain neuronal subtypes; and exhibit in vivo integration. Our work uniformly captures and maintains primitive neural stem cells from hESCs.
6. 判别出与肌肉修复有关的要害基因
【动态】
作为胚胎骨骼肌发育的要害，卫星细胞（SCs）直至婴儿期还在继续活跃的增添肌肉质量。之后，他们数目逐渐镌汰并悄然下来，直到损伤或退化激活它们增殖。卫星细胞维持肌肉生长并使成熟的骨骼肌具有强盛的再生能力。一项新的研究报告了Polycomb抑制性复合物2（PRC2）的酶亚基EZH2，在Pax7+/Myf5− 干细胞和 Pax7+/Myf5+ 肌原性前体细胞中都有表达，并且是坚持卫星细胞池稳固所需要的。有条件的切除SCs的Ezh2的老鼠出生后Pax7+细胞很少且肌肉数目下降还不可适当再生。这些缺陷与受损的SC增殖及非肌细胞中表达的基因的去抑制有联系。因此，EZH2在SCs中控制自我更新和增殖以及维持合适的转录程序。
【点评】
该研究对卫星细胞的增殖纪律以及肌肉损伤后修复有了更深入的相识，有助于损伤和朽迈肌肉回复的研究。
【参考论文】Genes Dev., 25:789%u2013794 DOI:10.1101/gad.2027911
Polycomb EZH2 controls self-renewal and safeguards the transcriptional identity of skeletal muscle stem cells
Juan AH, Derfoul A, Feng X, et al.
Satellite cells (SCs) sustain muscle growth and empower adult skeletal muscle with vigorous regenerative abilities. Here, we report that EZH2, the enzymatic subunit of the Polycomb-repressive complex 2 (PRC2), is expressed in both Pax7+/Myf5− stem cells and Pax7+/Myf5+ committed myogenic precursors and is required for homeostasis of the adult SC pool. Mice with conditional ablation of Ezh2 in SCs have fewer muscle postnatal Pax7+ cells and reduced muscle mass and fail to appropriately regenerate. These defects are associated with impaired SC proliferation and derepression of genes expressed in nonmuscle cell lineages. Thus, EZH2 controls self-renewal and proliferation, and maintains an appropriate transcriptional program in SCs.