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天下生命科学前沿动态周报（五十五）
（8.29-9.4/2011）
一竞技国际集团:陶国新
主要内容：端粒延伸替换机制不依赖端粒酶就可以维持端粒长度；人体结肠干细胞的疏散和体外增殖；微情形的脂肪细胞调理皮肤干细胞活性；内质网小管标记线粒体破碎位点；不可爆发和调动Lon卵白对抗氧化压力促使细胞朽迈；体外使用自身干细胞分解和作育红细胞用于输血。
焦点动态：人体结肠干细胞的疏散和体外增殖。
1. 端粒延伸替换机制不依赖端粒酶就可以维持端粒长度
【动态】
人类癌症亚型中保存一种维护端粒的端粒延伸替换机制（ALT）。约莫10%到15%的人类癌症检测不到端粒酶活性 ，其中一些通过被称为端粒延伸替换机制的不依赖端粒酶的端粒维护机制维持端粒长度。ALT表型在肉瘤和星形细胞瘤中相对较量普遍 ，而在上皮癌变中鲜有报道。不过 ，ALT的普遍性还没有在所有癌症类型中获得彻底判断。美国科学家就此在普遍的人类癌症中对ALT表型举行了综合视察。总共两个自力的样本群包括来自94种差别癌症亚型的6110例原发癌症 ，541例良性肿瘤 ，和264例正常组织通过端粒特异性的荧光原位杂交和免疫荧光标记PML卵白相团结的手艺举行了判断。总体上 ，在所有癌症样本中3.73%（228/6110）视察到ALT ，在良性肿瘤和正常组织中都没有视察到ALT。这是第一例报道ALT泛起在膀胱、子宫颈、子宫内膜、食道、胆囊、肾、肝和肺部的癌症中。别的 ，这也是第一例报道成神经管细胞瘤、少突神经胶质瘤、脑膜瘤、神经鞘瘤和小儿恶性胶质瘤中泛起ALT。先前的研究显示ALT状态和某些癌症的预后有关系 ，因此 ，需要进一步研究评估ALT阳性的肿瘤的潜在预后意义和奇异生物学。
【点评】
能够使用ALT途径的癌症预期会耐受抗端粒酶治疗 ，因此该研究的这些效果可能会对癌症治疗爆发影响 ，深入研究和明确 ALT途径的分子机理可能对设计针对使用ALT途径的癌症的药物有主要作用。
【参考论文】
The American Journal of Pathology, 2011, 179(4), DOI: 10.1016/j.ajpath.2011.06.018
Prevalence of the Alternative Lengthening of Telomeres Telomere Maintenance Mechanism in Human Cancer Subtypes
Christopher M. Heaphy, Andrea P. Subhawong, Seung-Mo Hong, et al.
Approximately 10% to 15% of human cancers lack detectable telomerase activity, and a subset of these maintain telomere lengths by the telomerase-independent telomere maintenance mechanism termed alternative lengthening of telomeres (ALT). The ALT phenotype, relatively common in subtypes of sarcomas and astrocytomas, has rarely been reported in epithelial malignancies. However, the prevalence of ALT has not been thoroughly assessed across all cancer types. We therefore comprehensively surveyed the ALT phenotype in a broad range of human cancers. In total, two independent sets comprising 6110 primary tumors from 94 different cancer subtypes, 541 benign neoplasms, and 264 normal tissue samples were assessed by combined telomere-specific fluorescence in situ hybridization and immunofluorescence labeling for PML protein. Overall, ALT was observed in 3.73% (228/6110) of all tumor specimens, but was not observed in benign neoplasms or normal tissues. This is the first report of ALT in carcinomas arising from the bladder, cervix, endometrium, esophagus, gallbladder, kidney, liver, and lung. Additionally, this is the first report of ALT in medulloblastomas, oligodendrogliomas, meningiomas, schwannomas, and pediatric glioblastoma multiformes. Previous studies have shown associations between ALT status and prognosis in some tumor types; thus, further studies are warranted to assess the potential prognostic significance and unique biology of ALT-positive tumors. These findings may have therapeutic consequences, because ALT-positive cancers are predicted to be resistant to anti-telomerase therapies.
2. 人体结肠干细胞的疏散和体外增殖
【动态】
在人体一生中 ，结肠干细胞每周再生更新一次大肠内层�？蒲Ъ壹甘昀粗な当４娼岢Ω上赴恢蔽薹ㄊ侗鸷团卸纤恰Ｎ靼嘌揽蒲Ъ易罱既范ㄎ涣巳闯Ω上赴谋４嫖恢貌⒖⒊隽艘惶滓炖词枭⒑吞逋庾饔� ，第一个报道了人体结肠上皮干细胞的疏散和体外作育增殖。细胞外貌B型蝶素受体（EPHB2）的差别含量使得能够从人体结肠粘膜活组织切片中疏散差别类型的细胞。细胞外貌含量最高的EPHB2 对应着具有最长端粒和高表达的肠干细胞（ISC）标记基因的结肠上皮细胞。并且 ，使用创立ISC微生态情形的作育条件 ，确实有一部分有高含量EPHB2的细胞能够在体外增殖成为不分解的多能细胞群。
【点评】
乐成疏散出结肠干细胞这种成体干细胞并体外作育恒久维持增殖不分解或定向分解 ，关于用成体干细胞建设体外模子研究胃肠道细胞的增殖分解开启了大门 ，也为探索更好的成体干细胞作育条件及着实际临床应用的转化打下了基础。
【参考论文】
Nature Medicine, 2011; DOI:10.1038/nm.2470
Isolation and in vitro expansion of human colonic stem cells
Peter Jung, Toshiro Sato, Anna Merlos-Suárez, et al.
Here we describe the isolation of stem cells of the human colonic epithelium. Differential cell surface abundance of ephrin type-B receptor 2 (EPHB2) allows the purification of different cell types from human colon mucosa biopsies. The highest EPHB2 surface levels correspond to epithelial colonic cells with the longest telomeres and elevated expression of intestinal stem cell (ISC) marker genes. Moreover, using culturing conditions that recreate the ISC niche, a substantial proportion of EPHB2-high cells can be expanded in vitro as an undifferentiated and multipotent population.
3. 微情形的脂肪细胞调理皮肤干细胞活性
【动态】
哺乳动物皮肤中需要多种类型成员细胞来形成有功效的组织并支持组织的稳固和再生。组成上皮干细胞微生态情形的细胞还不完全相识。美国科学家最近在皮肤中判断出脂肪前体细胞并证实它们的动态的再生平行于皮肤干细胞的激活�；加兄拘纬烧习睦鲜蟮囊约耙浦彩笛橹械闹鞠赴墓π饰雠⒄嫫つ诘闹鞠赴羌せ钅遗莞上赴某湟跫２⑶� ，未成熟脂肪细胞表达的PDGF可能在调理囊泡干细胞活性上起作用。这些数据凸显出天生脂肪的细胞是正向调理皮肤干细胞活性的皮肤微生态情形的组成细胞并提醒临床上脂肪细胞可能会改变上皮干细胞的功效。
【点评】
男性形态性秃发患者在毛囊根部尚有干细胞可是它们失去了启动毛发再生的能力 ，该研究证实形成皮肤干细胞微生态情形的脂肪细胞能够调理皮肤干细胞的活性 ，若是有步伐使这些脂肪细胞能够影响毛囊根部的干细胞 ，也许会促使毛发重新生长。另一方面 ，该研究的启示是皮肤干细胞的适合的生命情形是脂肪细胞组成的 ，皮肤干细胞的增殖分解需要的营养和信号也是脂肪细胞提供的。
【参考论文】
Cell, 2011; 146 (5): 761-771 DOI: 10.1016/j.cell.2011.07.019
Adipocyte Lineage Cells Contribute to the Skin Stem Cell Niche to Drive Hair Cycling
Eric Festa, Jackie Fretz, Ryan Berry, et al.
In mammalian skin, multiple types of resident cells are required to create a functional tissue and support tissue homeostasis and regeneration. The cells that compose the epithelial stem cell niche for skin homeostasis and regeneration are not well defined. Here, we identify adipose precursor cells within the skin and demonstrate that their dynamic regeneration parallels the activation of skin stem cells. Functional analysis of adipocyte lineage cells in mice with defects in adipogenesis and in transplantation experiments revealed that intradermal adipocyte lineage cells are necessary and sufficient to drive follicular stem cell activation. Furthermore, we implicate PDGF expression by immature adipocyte cells in the regulation of follicular stem cell activity. These data highlight adipogenic cells as skin niche cells that positively regulate skin stem cell activity, and suggest that adipocyte lineage cells may alter epithelial stem cell function clinically.
4. 内质网小管标记线粒体破碎位点
【动态】
线粒体通过破碎和融合调理自身结构和漫衍。线粒体破碎受控于Dnm1/Drp1 ，一个围绕线粒体形成螺旋调理破碎的与发动卵白相关的卵白。在线粒体网络中什么决议了破碎位点还很不清晰。内质网和线粒体体现出细密耦合的动力学和普遍的接触。加州大学的科学家研究了内质网是否在线粒体破碎中起作用。他们发明线粒体破碎爆发在内质网小管接触线粒体并调理招募Drp1前的缩短的位置。因此 ，内质网小管可能在界定线粒体破碎位点中起起劲的作用。
【点评】
线粒体维持正常功效关于细胞代谢是至关主要的 ，相识线粒体正常破碎的加入因素关于线粒体破碎障碍造成的功效缺陷的治疗有主要意义。
【参考论文】
Science, 2011; DOI: 10.1126/science.1207385
ER Tubules Mark Sites of Mitochondrial Division
Jonathan R. Friedman, Laura L. Lackner, Matthew West, et al.
Mitochondrial structure and distribution are regulated by division and fusion events. Mitochondrial division is regulated by Dnm1/Drp1, a dynamin-related protein that forms helices around mitochondria to mediate fission. Little is known about what determines sites of mitochondrial fission within the mitochondrial network. The endoplasmic reticulum (ER) and mitochondria exhibit tightly coupled dynamics and have extensive contacts. We tested whether ER plays a role in mitochondrial division. We found that mitochondrial division occurred at positions where ER tubules contacted mitochondria and mediated constriction prior to Drp1 recruitment. Thus, ER tubules may play an active role in defining the position of mitochondrial division sites.
5. 不可爆发和调动Lon卵白对抗氧化压力促使细胞朽迈
【动态】
美国科学家研究了Lon卵白诱导的朽迈Wi-38成纤维细胞中抵御氧化卵白积累的�；せ频乃鸹怠Ｏ吡Ｌ迓寻椎难趸鹕吮灰晕鼋嗦趵� ，而Lon卵白通常降解这些氧化损伤卵白。在早期的人体Wi-38成纤维细胞 ，过氧化氢压力会迅速诱导爆发Lon卵白 ，阻止积累氧化损伤卵白 ，�；は赴盍ΑＯ喾吹� ，中期细胞在氧化压力下只体现出缓慢的诱导爆发Lon卵白 ，氧化损伤卵白最先积累。后期或朽迈的细胞 ，Lon卵白基础水平很低 ，积累的氧化损伤卵白水平很高 ，对氧化压力的反应中它们不可诱导爆发Lon卵白 ，体现出一连增添的氧化损伤卵白积累。朽迈细胞破碎成两群 ，一群体现出正常的线粒体质量而另一群体现出显着的线粒体丧失。两群细胞的线粒体跨膜电位都削弱了。这些朽迈的转变类似于在年轻细胞中关闭Lon基因造成的效果。据此研究者建议Lon卵白爆发的压力诱导性的损失是使细胞偏向朽迈的弱化的压力顺应能力模式的一部分。
【点评】
该研究部分诠释了造成线粒体卵白氧化和细胞朽迈的缘故原由。Lon卵白作为主要的线粒体抗氧化卵白是其中的要害因素。一竞技再生物质能够增强线粒体数目和功效 ，在这个意义上 ，增进Lon卵白的爆发 ，阻止积累氧化损伤卵白 ，�；は赴盍� ，坚持细胞不朽迈。
【参考论文】
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2011; DOI: 10.1093/gerona/glr145
Impairment of Lon-Induced Protection Against the Accumulation of Oxidized Proteins in Senescent Wi-38 Fibroblasts
J. K. Ngo, L. C. D. Pomatto, D. A. Bota, et al.
Oxidative damage to mitochondrial proteins is thought to contribute to the aging process, but the Lon protease normally degrades such proteins. In early-passage WI-38 human lung fibroblasts, Lon expression is rapidly induced during H2O2 stress, which prevents the accumulation of oxidized proteins and protects cell viability. In contrast, middle passage cells exhibit only sluggish induction of Lon expression in oxidative stress, and oxidized proteins initially accumulate. Late-passage, or senescent, cells have low basal levels of Lon and high levels of accumulated oxidized proteins; in response to oxidative stress, they fail to induce Lon expression and exhibit continually increasing accumulation of oxidized proteins. Senescent cells separated into two populations, one exhibiting normal mitochondrial mass and a second displaying significant loss of mitochondria; both populations had diminished mitochondrial transmembrane potential. These senescent changes are similar to the effects of Lon silencing in young cells. We suggest that loss of Lon stress inducibility is part of a pattern of diminishing stress adaptability that predisposes cells to senescence.
6. 体外使用自身干细胞分解和作育红细胞用于输血
【动态】
干细胞体外生产红血球可能会是取代古板输血用血的一种选择。这一看法的临床可行性尚未剖析。法国科学家最近的研究就这一问题给出了起源一定的谜底。他们使用一种作育计划允许外周CD34+造血干细胞分解为网织红细胞 ，生产了同种的作育的红细胞 ，在变形性、酶含量、其血红卵白团结和释放氧气的能力以及表达血型抗原方面都有功效。此后在老鼠体内证实作育的红细胞在体内遇到了使其完全成熟所需的条件。临床研究中注射入人体内的作育红细胞存活半衰期类似于自然的红细胞 ，证实晰它们的质量和功效性。
【点评】
体外使用自身干细胞分解和作育红细胞用于输血 ，可能有助于解决血源问题和免疫倾轧问题。
【参考论文】
Blood, 2011; DOI: 10.1182/blood-2011-06-362038
Proof of principle for transfusion of in vitro generated red blood cells
Marie-Catherine Giarratana, Hélène Rouard, Agnès Dumont, et al.
In vitro red blood cell (RBC) production from stem cells could represent an alternative to classical transfusion products. Up until now the clinical feasibility of this concept has not been demonstrated. We addressed the question of the capacity of cultured RBC (cRBC) to survive in human. Using a culture protocol permitting erythroid differentiation from peripheral CD34+ HSC, we generated a homogeneous population of cRBC functional in terms of their deformability, enzyme content, capacity of their hemoglobin to fix/release oxygen and expression of blood group antigens. We then demonstrated in the NOD/SCID mouse that cRBC encountered in vivo the conditions necessary for their complete maturation. These data provided the rationale for injecting into one human a homogeneous sample of 1010 cRBC generated under GMP conditions and labeled with 51Cr. The level of these cells in the circulation 26 days after injection lies between 41 and 63 % which compares favorably to the reported half-life of 28 ± 2 days for native RBC. Their survival in vivo testifies globally to their quality and functionality. These data establish the proof of principle for transfusion of in vitro generated RBC and path the way towards new developments in transfusion medicine. This study has been registered at clinicaltrials.gov as NCT0929266.