世界生命科学前沿动态周报（二十一）

（08.23 --08.29/ 2010）
美宝国际集团:陶国新 

　　本周动态包括以下内容： 体内葡萄糖含量过高影响免疫系统 ; MIT 科学家发明人类干细胞培养新方法； 骨髓移植治疗 大疱性表皮松解症； 生物合成角膜有助视力恢复；科学家 确认血脂代谢相关基因座 。

•  体内葡萄糖含量过高影响免疫系统
【摘要】 来源：科技日报 发布时间： 2010-8-27 17:13:23

　　糖尿病患者除易患肾脏疾病等并发症外，也很容易被慢性细菌和真菌感染而患上炎症性疾病。对于这类并发症的病理机制，医学界一直不太清楚。英国华威大学最新研究表明，这是由于人体内葡萄糖水平过高影响了免疫系统，抑制其功能发挥造成的。华威大学 8 月 25 日发布的公报中称，该校研究人员对人体血液和体液中的葡萄糖和另外两种糖——甘露糖和岩藻糖的化学结构进行了分析。甘露糖和岩藻糖是人体免疫受体识别细菌和真菌的标记，免疫受体会与这两种微糖绑定来对抗感染。研究人员发现，人体内葡萄糖水平一旦过高，其就会代替甘露糖和岩藻糖绑定免疫受体，从而妨碍免疫受体识别感染性细菌和真菌。这种越俎代庖的行为，会抑制人体对抗感染的正常进程。它会抑制人体免疫系统 C 型凝集素的功能。这些凝集素中，包括甘露糖结合凝集素（ MBL ），其功能失效，则会使人更易患上炎症性疾病；它也会影响免疫细胞表面受体 DC-SIGN 和 DC-SIGNR ，这两种受体存在于白血球、血小板、血管内皮细胞等循环和血管系统的关键部位中，它们的功能受到抑制，则会导致糖尿病人出现心血管和肾脏并发症。  

　　华威大学医学院的丹尼尔· 米切尔 博士表示，葡萄糖水平与人体免疫系统之间的这种关系，使科学家对高葡萄糖对免疫系统和身体健康的影响有了新的认识。而日常生活中保持合理的饮食结构，控制血糖水平则更显得重要。他们将基于新发现来完善糖尿病疾病模型，以寻找新的防治手段。

【点评】

　　该项研究发现了人体内 高水平葡萄糖会通过竞争性抑制来干扰免疫受体对寡糖的体识，进而妨碍免疫受体识别感染性细菌和真菌，抑制人体对抗感染的正常进程。对于人类，尤其是糖尿病人，重新认识高血糖的生理意义及其对糖尿病并发症的作用有重要影响。同时也提醒人们日常饮食摄入过多的糖分很可能会降低你的身体免疫力。

【原文摘录 】   Immunobiology doi:10.1016/j.imbio.2010.06.002 

High glucose disrupts oligosaccharide recognition function via competitive inhibition: A potential mechanism for immune dysregulation in diabetes mellitus.

Ilyas R , Wallis R , Soilleux EJ , et al.

Diabetic complications include infection and cardiovascular disease. Within the immune system, host-pathogen and regulatory host-host interactions operate through binding of oligosaccharides by C-type lectin. A number of C-type lectins recognise oligosaccharides rich in mannose and fucose - sugars with similar structures to glucose. This raises the possibility that high glucose conditions in diabetes affect protein-oligosaccharide interactions via competitive inhibition. Mannose-binding lectin, soluble DC-SIGN and DC-SIGNR, and surfactant protein D, were tested for carbohydrate binding in the presence of glucose concentrations typical of diabetes, via surface plasmon resonance and affinity chromatography. Complement activation assays were performed in high glucose. DC-SIGN and DC-SIGNR expression in adipose tissues was examined via immunohistochemistry. High glucose inhibited C-type lectin binding to high-mannose glycoprotein and binding of DC-SIGN to fucosylated ligand (blood group B) was abrogated in high glucose. Complement activation via the lectin pathway was inhibited in high glucose and also in high trehalose - a nonreducing sugar with glucoside stereochemistry. DC-SIGN staining was seen on cells with DC morphology within omental and subcutaneous adipose tissues. We conclude that high glucose disrupts C-type lectin function, potentially illuminating new perspectives on susceptibility to infectious and inflammatory disease in diabetes. Mechanisms involve competitive inhibition of carbohydrate binding within sets of defined proteins, in contrast to broadly indiscriminate, irreversible glycation of proteins.

•  MIT 科学家发明人类干细胞培养新方法

【摘要】

　　多功能干细胞能够分化成其他任何一种体细胞，在治疗各种疾病方面具有很大潜力。但是，如何培养足够量的多功能干细胞对研究者来说是个问题；此外，目前用于培养人类干细胞的材料会导致免疫反应。为了克服这些问题，以美国麻省理工学院（ MIT ）科学家为首的研究小组发明了一种合成性基质（ synthetic substrate ）。这种基质没有外来动物材料，能够使干细胞至少三个月保持活性并自我繁殖。而且，该合成性基质首次使得单细胞能够形成细胞集落。相关研究发表在 8 月 22 日的《自然—材料学》（ Nature Materials ）上。

　　以往研究表明，基质表面的化学和物理特性，比如粗糙度、硬度、对水的亲和力等对干细胞生长有影响。 MIT 研究人员创造了 500 种特性不同的聚合物并在上面培养干细胞，分析每个聚合物上面细胞的生长状况。他们发现， 基质表面疏水性 对细胞生长有个最佳范围，而表面糙度和硬度则没有太多影响。此外，他们调整最佳聚合物的组成为：高比例的丙烯酸酯，外面包裹玻连蛋白。应用这种新的培养基质， MIT 科学家成功实现了人类胚胎干细胞持续三个月的生长和分裂，并获得了大量的细胞。他们将进一步研究，争取将这种培养基质应用到其它类细胞。（ 来源： 科学网 www.sciencenet.cn 发布时间： 2010-8-24 10:43:34 ）

【点评】

　　新的培养基质可以使干细胞长时间保持活性和自我繁殖，对于解决干细胞研究中获取大量干细胞的问题有很大帮助。虽然不能因此使干细胞治疗有实质性进展，但至少有助于干细胞的实验研究。

【原文摘录】 Nature Materials 9, 768–778 doi:10.1038/nmat2812

Combinatorial development of biomaterials for clonal growth of human pluripotent stem cells

Ying Mei , Krishanu Saha , Said R. Bogatyrev ， et al.

Both human embryonic stem cells and induced pluripotent stem cells can self-renew indefinitely in culture; however, present methods to clonally grow them are inefficient and poorly defined for genetic manipulation and therapeutic purposes. Here we develop the first chemically defined, xeno-free, feeder-free synthetic substrates to support robust self-renewal of fully dissociated human embryonic stem and induced pluripotent stem cells. Material properties including wettability, surface topography, surface chemistry and indentation elastic modulus of all polymeric substrates were quantified using high-throughput methods to develop structure–function relationships between material properties and biological performance. These analyses show that optimal human embryonic stem cell substrates are generated from monomers with high acrylate content, have a moderate wettability and employ integrin α v β 3 and α v β 5 engagement with adsorbed vitronectin to promote colony formation. The structure–function methodology employed herein provides a general framework for the combinatorial development of synthetic substrates for stem cell culture.

•  骨髓移植治疗 大疱性表皮松解症
【摘要】 NEJM 发布时间： 2010-8-25 15:33:04

　　大疱性表皮松解症是由于皮肤结构蛋白的先天性缺陷，使皮肤容易发生松解出现大疱。如单纯性大疱性表皮松解症是由于表皮基底细胞的结构蛋白 -- 角蛋白 5 或角蛋白 14 的缺陷所致；交界性大疱性表皮松解症是由于 BPAG2 或板素 (Laminin)5 的缺陷所致；营养不良型大疱性表皮松解症则是由于基底膜带中 Ⅶ 型胶原蛋白的缺陷所致。现已弄清缺陷的发生是因为这些编码蛋白的基因出现了突变，导致蛋白质的结构异常，使皮肤松解。尽管遗传学基础已被阐明，但仍无有效的治疗。大疱性表皮松解的治疗主要针对其继发感染，原则为精心护理，保护局部，避免外伤、摩擦受热防止继发感染。利用干细胞产生新的组织和器官，修复破损的组织、器官，被称为再生医学。 美国《新英格兰医学杂志》（ NEJM ） 8 月 11 日刊登明尼苏达大学研究者约翰· 瓦格纳和雅各布·托拉尔的研究报告，首次显示骨髓干细胞可用于治疗营养不良型大疱性表皮松解症，为根除这一顽疾带来了希望。

【点评】

　　用于 6 名大疱性表皮松解症患者的同种异体骨髓移植的实验性临床治疗为从根本上治愈这一顽症提供了一种可能，尽管这一方法的长期风险和效果还有待进一步评估。另一方面，该研究也提示该治疗中骨髓干细胞可能是分化成正常皮肤组织的来源。

【原文摘录 】 N Engl J Med 2010; 363:629-639 August 12, 2010

Bone Marrow Transplantation for Recessive Dystrophic Epidermolysis Bullosa

John E. Wagner, M.D., Akemi Ishida-Yamamoto, M.D., Ph.D., John A. McGrath, M.D., et al.

Background

Recessive dystrophic epidermolysis bullosa is an incurable, often fatal mucocutaneous blistering disease caused by mutations in COL 7A 1, the gene encoding type VII collagen (C7). On the basis of preclinical data showing biochemical correction and prolonged survival in col7 −/− mice, we hypothesized that allogeneic marrow contains stem cells capable of ameliorating the manifestations of recessive dystrophic epidermolysis bullosa in humans.

Methods

Between October 2007 and August 2009, we treated seven children who had recessive dystrophic epidermolysis bullosa with immunomyeloablative chemotherapy and allogeneic stem-cell transplantation. We assessed C7 expression by means of immunofluorescence staining and used transmission electron microscopy to visualize anchoring fibrils. We measured chimerism by means of competitive polymerase-chain-reaction assay, and documented blister formation and wound healing with the use of digital photography.

Results

One patient died of cardiomyopathy before transplantation. Of the remaining six patients, one had severe regimen-related cutaneous toxicity, with all having improved wound healing and a reduction in blister formation between 30 and 130 days after transplantation. We observed increased C7 deposition at the dermal–epidermal junction in five of the six recipients, albeit without normalization of anchoring fibrils. Five recipients were alive 130 to 799 days after transplantation; one died at 183 days as a consequence of graft rejection and infection. The six recipients had substantial proportions of donor cells in the skin, and none had detectable anti-C7 antibodies.

Conclusions

Increased C7 deposition and a sustained presence of donor cells were found in the skin of children with recessive dystrophic epidermolysis bullosa after allogeneic bone marrow transplantation. Further studies are needed to assess the long-term risks and benefits of such therapy in patients with this disorder.

•  生物合成角膜有助视力恢复
【摘要】 来源：《科学—转化医学》 发布时间： 2010-8-27 16:22:22

　　加拿大和瑞典科研人员研制出一种生物合成角膜，帮助眼疾患者修复受损眼组织，恢复视力。由加拿大渥太华医院研究所研究员梅·格里菲思和瑞典林雪平大学眼科学教授佩尔·法格霍尔姆领导的一个研究小组将 10 名患者角膜中的受损组织移除后，植入人造角膜。术后，研究人员经过两年多的跟踪观察，发现其中 9 名患者的人造角膜与眼球其他细胞融合。研究人员说，接受移植后的眼球开始分泌泪液。 6 名患者的视力逐渐恢复。“这项研究第一次表明，人造角膜可以与人的眼球融合并激发组织再生 , ”格里菲斯说：“随着研究的深入，这种方式能帮助数以百万计等待角膜移植的人恢复视力。”角膜是眼球表面覆盖的一层透明、胶片状组织，主要成分是蛋白胶原质，能够折射光线，将景物成像于视网膜上。尽管角膜容易受到外伤或感染而受损，但眼下的医学技术能够通过角膜移植手术令患者恢复视力。研究人员说，由于眼角膜捐献数量有限，全球每年有许多人因角膜受伤致残。他们这项研究成果有助于这些眼疾患者重见光明。

【点评】

　　两年多跟踪观察 10 名移植了人造角膜的患者， 9 名患者的人造角膜与眼球其他细胞融合， 6 名患者的视力逐渐恢复。长期效果有待观察，但这项研究第一次表明，人造角膜可以与人的眼球融合并激发组织再生，有可能帮助因角膜受伤致残患者重见光明。在医用材料而言是一大突破。

【原文摘录 】 Sci Transl Med Vol. 2, Issue 46, p. 46ra61 DOI: 10.1126/scitranslmed.3001022

A Biosynthetic Alternative to Human Donor Tissue for Inducing Corneal Regeneration: 24-Month Follow-Up of a Phase 1 Clinical Study

Per Fagerholm , Neil S. Lagali , Kimberley Merrett , et al.

Corneas from human donors are used to replace damaged tissue and treat corneal blindness, but there is a severe worldwide shortage of donor corneas. We conducted a phase 1 clinical study in which biosynthetic mimics of corneal extracellular matrix were implanted to replace the pathologic anterior cornea of 10 patients who had significant vision loss, with the aim of facilitating endogenous tissue regeneration without the use of human donor tissue. The biosynthetic implants remained stably integrated and avascular for 24 months after surgery, without the need for long-term use of the steroid immunosuppression that is required for traditional allotransplantation. Corneal reepithelialization occurred in all patients, although a delay in epithelial closure as a result of the overlying retaining sutures led to early, localized implant thinning and fibrosis in some patients. The tear film was restored, and stromal cells were recruited into the implant in all patients. Nerve regeneration was also observed and touch sensitivity was restored, both to an equal or to a greater degree than is seen with human donor tissue. Vision at 24 months improved from preoperative values in six patients. With further optimization, biosynthetic corneal implants could offer a safe and effective alternative to the implantation of human tissue to help address the current donor cornea shortage.

•  科学家确认血脂代谢相关基因座
【摘要】 《自然》 发布时间： 2010-8-25 17:47:46

　　血液中总胆固醇、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇和甘油三酯等脂类含量是导致冠状动脉疾病（ CAD ）的最重要危险因素，同时也是防治该种疾病的重要标靶。一国际研究小组在《自然》（ Nature ）杂志上刊登报告称，他们研究确认了 95 个与人类血脂代谢相关的基因座，可作为冠状动脉疾病的生物学标记。研究人员称，新研究不仅扩展了科学家对人体脂类代谢的理解视野，同时也为开发新型防治冠状动脉疾病的靶向型药物奠定了基础。 该国际研究小组由英美等多国近百位科学家组成，他们对超过 10 万名具有欧洲血统的志愿者的基因进行了分析，最终确认了 95 个与脂类代谢相关的基因座，其中有 59 个基因座是首次被认定。这 95 个基因座不仅会导致人体内脂类特性的一般性改变，而且还会导致极端的脂类表型。研究结果表明，一些新发现的基因座与冠状动脉疾病有关。研究人员还就 GALNT2 、 PPP1R3B 和 TTC39B 这三种新基因在小鼠模型上进行了验证。  

　　研究人员表示，此项研究是目前就人体脂类代谢机制生物学基础问题所进行的最全面的分析研究，其目的是要找到血液中脂类聚集的生物学标记，以作为冠状动脉疾病发展的指标。研究结果则表明，通过抑制这些与脂类代谢有关的关键基因，可以起到预防心脏疾病的作用，这为开发新的靶向型药物提供了基础。英国伦敦国王大学的马西莫·曼 吉诺 博士指出，这项研究对于科学家掌握冠状动脉疾病的风险因素很有帮助。虽然研究对象是具有欧洲血统的志愿者，但研究人员发现，这些基因座并非欧洲人独有，其对三个非欧洲人群体（东亚人、南亚人以及非洲裔美国人）的脂类特性也会产生重要影响。作为此方面迄今为止最大规模的研究，超大的样本量使得该结果同样具有国际意义。（来源：科技日报 刘海英 / 刘霞）

【点评】

　　作为就人体脂类代谢机制生物学基础问题所进行超大样本量的最全面的分析研究，对于科学家掌握冠状动脉疾病的风险因素很有帮助。但是否因此就能发展出更好的治疗冠状动脉疾病的疗法或药物还看不出来。

【原文摘录 】 Nature doi:10.1038/nature09270
Biological, clinical and population relevance of 95 loci for blood lipids

Tanya M. Teslovich , Kiran Musunuru , Albert V. Smith , et al.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci ( P < 5 × 10 −8 ), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP 7A 1 , NPC 1L 1 and SCARB1 ) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes— GALNT2 , PPP1R3B and TTC39B —with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.