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天下生命科学前沿动态周报（四十七）
（7.4-7.10/2011）
一竞技国际集团:陶国新
主要内容：有吸收功效的组织工程小肠；第一次疏散出单个纯的人体血液干细胞；乙酰辅酶A水平影响细胞生长增殖；卵巢上皮细胞癌变历程中生物力学特征的转变；中枢神经系统损伤后形成的疤痕泉源于周细胞；间充质干细胞--体内的创伤药房。
焦点动态：乙酰辅酶A水平影响细胞生长增殖。
1. 有吸收功效的组织工程小肠
【动态】
最近，洛杉矶儿童医院的科学家通过组织工程手段在老鼠身上制造了有功效的小肠，希望未来能用于治疗短肠综合症。在他们最新揭晓的“一种多细胞要领在老鼠中形成足够量的组织工程小肠”文章中报道了他们能在老鼠中生长组织工程小肠。小肠是一个很是精巧的具有再生能力的器官，在我们一生中小肠细胞一直更新。这些科学家使用了小肠的这种再生能力，将取自两周大绿色荧光标记的供体转基因老鼠的类器官单位（包括形成小肠的种种类型细胞的混淆物，包括肌细胞和上皮细胞）加载到生物降解质料做成的支架上，此后植入3到6个月大的完全无免疫力的转基因老鼠模子腹内，凭证绿色荧光标记追踪植入细胞的生长情形，由植入细胞天生的种种细胞群最终形成了包括所有主要细胞类型，肌细胞、神经细胞、四种类型上皮细胞和部分血管，类似于自然小肠结构的具有吸收功效的组织工程小肠。
【点评】
这个实验的效果很令人兴奋，相当于通详尽胞移植在体内作育出起作用的小肠。可是思量到实验是在完全无免疫力的老鼠而非正常老鼠身上获得这一效果的，其价值尤其是应用远景就大打折扣了。
【参考论文】Tissue Engineering Part A, 2011; 17 (13-14): 1841 DOI:10.1089/ten.tea.2010.0564
A Multicellular Approach Forms a Significant Amount of Tissue-Engineered Small Intestine in the Mouse
Frédéric G. Sala, Jamil A. Matthews, Allison L. Speer, et al.
Tissue-engineered small intestine (TESI) has successfully been used to rescue Lewis rats after massive small bowel resection. In this study, we transitioned the technique to a mouse model, allowing investigation of the processes involved during TESI formation through the transgenic tools available in this species. This is a necessary step toward applying the technique to human therapy. Multicellular organoid units were derived from small intestines of transgenic mice and transplanted within the abdomen on biodegradable polymers. Immunofluorescence staining was used to characterize the cellular processes during TESI formation. We demonstrate the preservation of Lgr5- and DcamKl1-positive cells, two putative intestinal stem cell populations, in proximity to their niche mesenchymal cells, the intestinal subepithelial myofibroblasts (ISEMFs), at the time of implantation. Maintenance of the relationship between ISEMF and crypt epithelium is observed during the growth of TESI. The engineered small intestine has an epithelium containing a differentiated epithelium next to an innervated muscularis. Lineage tracing demonstrates that all the essential components, including epithelium, muscularis, nerves, and some of the blood vessels, are of donor origin. This multicellular approach provides the necessary cell population to regenerate large amounts of intestinal tissue that could be used to treat short bowel syndrome.
2. 第一次疏散出单个纯的人体血液干细胞
【动态】
科学杂志最新揭晓的加拿大科学家的研究显示发明干细胞50年来，第一次以单个细胞形式疏散出最纯的人体血液干细胞，能够再生整个血液系统，极大的增补了血液系统发育的线路图。血液细胞的终生生产依赖于少少的造血干细胞，经由一系列差别细胞系的过渡状态，一连增补成熟细胞。可是关于造血干细胞的研究一直受困于无法从多能祖细胞中将其纯化出来。加拿大的这项研究找到了造血干细胞的特殊标记物CD49f，从而能够将其以单个细胞的形式纯化出来。这将大大增进关于造血干细胞生命纪律的研究以及临床治疗用途的开发。
【点评】
能够彻底纯化人体造血干细胞无论是对干细胞的基础研究照旧对干细胞临床应用开发都是一个突破性希望。这一发明最终准确定位了整个血液系统的起源地。
【参考论文Science, 2011; 333 (6039): 218 DOI:10.1126/science.1201219
Isolation of Single Human Hematopoietic Stem Cells Capable of Long-Term Multilineage Engraftment
F. Notta, S. Doulatov, E. Laurenti, et al.
Lifelong blood cell production is dependent on rare hematopoietic stem cells (HSCs) to perpetually replenish mature cells via a series of lineage-restricted intermediates. Investigating the molecular state of HSCs is contingent on the ability to purify HSCs away from transiently engrafting cells. We demonstrated that human HSCs remain infrequent, using current purification strategies based on Thy1 (CD90) expression. By tracking the expression of several adhesion molecules in HSC-enriched subsets, we revealed CD49f as a specific HSC marker. Single CD49f+ cells were highly efficient in generating long-term multilineage grafts, and the loss of CD49f expression identified transiently engrafting multipotent progenitors (MPPs). The demarcation of human HSCs and MPPs will enable the investigation of the molecular determinants of HSCs, with a goal of developing stem cell–based therapeutics.
3. 乙酰辅酶A水平影响细胞生长增殖
【动态】
美国科学家最近发明乙酰辅酶A通过增进生长基因上的组卵白乙�；从盏枷赴ず驮鲋�。细胞进入生长和分解的决议必需与其可用营养和代谢状态亲近配合。这些代谢和营养方面的要求条件及其诱导细胞生长增殖的机理还很不清晰。美国科学家报道了乙酰辅酶A作为碳源的下游代谢产品代表了一种有关生长增殖的要害代谢信号。在进入生长周期时，细胞内乙酰辅酶A的水平有实质性增添效果诱导主要的生长基因上的组卵白举行Gcn5p/SAGA 催化的乙�；�，由此促使他们能够快速转录并致力于细胞生长。 因此，乙酰辅酶A起到碳源“变阻器”的作用，通过增进生长基因上的特殊组卵白的乙�；雌舳赴こ绦�。
【点评】
细胞内乙酰辅酶A的水平影响生长基因上的组卵白的乙�；�，进而影响细胞进入生长和分解的决议。营养和代谢状态决议着细胞生长和增殖，乙酰辅酶A作为要害代谢信号起主要作用。
【参考论文】Molecular Cell, 2011 42(4): 426-437
Acetyl-CoA Induces Cell Growth and Proliferation by Promoting the Acetylation of Histones at Growth Genes
Ling Cai, Benjamin M. Sutter, Bing Li, and Benjamin P. Tu
The decision by a cell to enter a round of growth and division must be intimately coordinated with nutrient availability and its metabolic state. These metabolic and nutritional requirements, and the mechanisms by which they induce cell growth and proliferation, remain poorly understood. Herein, we report that acetyl-CoA is the downstream metabolite of carbon sources that represents a critical metabolic signal for growth and proliferation. Upon entry into growth, intracellular acetyl-CoA levels increase substantially and consequently induce the Gcn5p/SAGA-catalyzed acetylation of histones at genes important for growth, thereby enabling their rapid transcription and commitment to growth. Thus, acetyl-CoA functions as a carbon-source rheostat that signals the initiation of the cellular growth program by promoting the acetylation of histones specifically at growth genes.
4. 卵巢上皮细胞癌变历程中生物力学特征的转变
【动态】
癌细胞侵袭性的体现被以为是除遗传转变外，还与生物力学和细胞骨架结构的改变有关。美国科学家的一项最新研究测定了老鼠卵巢外貌上皮细胞癌变历程中细胞的粘弹性的转变，发明在它们照旧良性的时间更硬更粘，细胞变形性的增添直接与癌变历程相关。细胞骨架结构中肌动卵白水平的下降直接与细胞生物力学性子的转变相关。差别癌症阶段的差别生物力学体现有助于癌症的诊断、危害评估和提高治疗效果。该研究中，癌变细胞相比未癌变的康健细胞，显得更软和变形更快，流动性也增添了。
【点评】
细胞生物力学性子的转变展现了癌症的生长阶段，将生物学问题的物理学特征泛起出来�Ｌ沟戳税┲⒀芯恳灾律镅а芯康氖右�，也有助于重新的角度研究息争决癌症难题。
【参考论文】Nanomedicine: Nanotechnology, Biology and Medicine, 2011; doi: 10.1016/j.nano.2011.05.012
The effects of cancer progression on the viscoelasticity of ovarian cell cytoskeleton structures
Alperen N. Ketene, Eva M. Schmelz, Paul C. Roberts, Masoud Agah
Alterations in the biomechanical properties and cytoskeletal organization of cancer cells in addition to genetic changes have been correlated with their aggressive phenotype. In this study, we investigated changes in the viscoelasticity of mouse ovarian surface epithelial (MOSE) cells, a mouse model for progressive ovarian cancer. We demonstrate that the elasticity of late-stage MOSE cells (0.549 ± 0.281 kPa) were significantly less than that of their early-stage counterparts (1.097 ± 0.632 kPa). Apparent cell viscosity also decreased significantly from early (144.7 ± 102.4 Pa-s) to late stage (50.74 ± 29.72 Pa-s). This indicates that ovarian cells are stiffer and more viscous when they are benign. The increase in cell deformability directly correlates with the progression of a transformed phenotype from a nontumorigenic, benign cell to a tumorigenic, malignant one. The decrease in the level of actin in the cytoskeleton and its organization is directly associated with the changes in cell biomechanical property.
5. 中枢神经系统损伤后形成的疤痕泉源于周细胞
【动态】
瑞典科学家在最近的科学杂志上报道了他们发明了中枢神经损伤后形成疤痕组织的细胞泉源是周细胞。中枢神经损伤后缺损组织的再生能力很有限，损伤会被疤痕组织关闭。由于此疤痕组织富含星形胶质细胞，常被以为是神经胶质疤痕，其作用重大，被探讨了一个多世纪了。该研究发明在受伤脊髓中形成疤痕的基质细胞是由一种特殊亚型的周细胞派生来的，在伤处该周细胞数目多于星形胶质细胞。阻断该细胞的繁衍会使受伤组织无法闭合。该发明提供了一种组织纤维化的细胞泉源。
【点评】
中枢神经损伤后形成的疤痕组织泉源于周细胞的发明，有助于增进神经损伤修复的研究。
【参考论文】Science 8 July 2011: Vol. 333 no. 6039 pp. 238-242，DOI: 10.1126/science.1203165
A Pericyte Origin of Spinal Cord Scar Tissue
Christian Göritz, David O. Dias, Nikolay Tomilin, et al.
There is limited regeneration of lost tissue after central nervous system injury, and the lesion is sealed with a scar. The role of the scar, which often is referred to as the glial scar because of its abundance of astrocytes, is complex and has been discussed for more than a century. Here we show that a specific pericyte subtype gives rise to scar-forming stromal cells, which outnumber astrocytes, in the injured spinal cord. Blocking the generation of progeny by this pericyte subtype results in failure to seal the injured tissue. The formation of connective tissue is common to many injuries and pathologies, and here we demonstrate a cellular origin of fibrosis.
6. 间充质干细胞--体内的创伤药房
【动态】
研究批注体内间充质干细胞位于血管周，只关注它们多向分解能力的古板看法也该扩展到包括那些拓宽其治疗远景的同样吸引人的功效如细胞调理。细胞杂志的一篇综述就此问题的已有证据举行了研究，效果发明在局部损伤中，间充质干细胞从血管周的位置释放出来，激活，通过渗透生物活性分子和调理局部免疫反应建设再生的微情形。这些营养和免疫调理行为显示间充质干细胞可能充当了体内管理损伤部位的“药房”。这一能够形成多种差别组织的干细胞在起自然�；ぁ⒅瘟坪蜕股氐淖饔�。
【点评】
间充质干细胞越来越多的主要作用被展现出来，充辩白明该种干细胞在体内的主要意义，怎样体内营造适于它生涯的情形应该成为施展其心理功效的主要研究课题。
【参考论文】Cell Stem Cell, Volume 9, Issue 1, 11-15, 8 July 2011 DOI: 10.1016/j.stem.2011.06.008
The MSC: An Injury Drugstore
Arnold I. Caplan, Diego Correa
Now that mesenchymal stem cells (MSCs) have been shown to be perivascular in vivo, the existing traditional view that focuses on the multipotent differentiation capacity of these cells should be expanded to include their equally interesting role as cellular modulators that brings them into a broader therapeutic scenario. We discuss existing evidence that leads us to propose that during local injury, MSCs are released from their perivascular location, become activated, and establish a regenerative microenvironment by secreting bioactive molecules and regulating the local immune response. These trophic and immunomodulatory activities suggest that MSCs may serve as site-regulated drugstores in vivo.