世界生命科学前沿动态周报（四十）

【点评】
　尽管没有使用iPS细胞，而是直接从皮肤细胞诱导形成的类软骨细胞，在老鼠体内还是有部分形成了肿瘤。这种使用仅知的少数诱导因子来变换细胞类别的方法目前还很难控制这一变化形成的是健康细胞。

【参考论文】Journal of Clinical Investigation, 2011; DOI: 10.1172/JCI44605
Generation of hyaline cartilaginous tissue from mouse adult dermal fibroblast culture by defined factors
Kunihiko Hiramatsu, Satoru Sasagawa, Hidetatsu Outani, et al.
Repair of cartilage injury with hyaline cartilage continues to be a challenging clinical problem. Because of the limited number of chondrocytes in vivo, coupled with in vitro de-differentiation of chondrocytes into fibrochondrocytes, which secrete type I collagen and have an altered matrix architecture and mechanical function, there is a need for a novel cell source that produces hyaline cartilage. The generation of induced pluripotent stem (iPS) cells has provided a tool for reprogramming dermal fibroblasts to an undifferentiated state by ectopic expression of reprogramming factors. Here, we show that retroviral expression of two reprogramming factors (c-Myc and Klf4) and one chondrogenic factor (SOX9) induces polygonal chondrogenic cells directly from adult dermal fibroblast cultures. Induced cells expressed marker genes for chondrocytes but not fibroblasts, i.e., the promoters of type I collagen genes were extensively methylated. Although some induced cell lines formed tumors when subcutaneously injected into nude mice, other induced cell lines generated stable homogenous hyaline cartilage–like tissue. Further, the doxycycline-inducible induction system demonstrated that induced cells are able to respond to chondrogenic medium by expressing endogenous Sox9 and maintain chondrogenic potential after substantial reduction of transgene expression. Thus, this approach could lead to the preparation of hyaline cartilage directly from skin, without generating iPS cells.

3. IRF5双向调节免疫反应
【动态】
　　编码提高mRNA表达的转录因子IRF5的基因多态性与许多自体免疫疾病相关。英国科学家最近发现IRF5蛋白在特定白细胞中起到“主开关”的作用，决定这些白细胞是促进还是抑制炎症。炎症反应是机体抵御象感染和组织损伤等有害刺激的重要手段，但是在很多情况下，过度发炎本身也会损害机体，像类风湿关节炎。免疫系统的巨噬细胞既能刺激发炎也能通过释放化学信号改变其他细胞的行为来抑制炎症。而本研究表明IRF5蛋白是决定巨噬细胞如何作用的分子开关。结果显示在巨噬细胞中阻断IRF5蛋白的产生可能会是一种治疗一大群自体免疫疾病的有效方法。另外，提升IRF5蛋白水平可能有助于治疗免疫系统功能低下。IRF5可能是通过激活那些刺激炎症反应的基因和抑制相反功能的基因来起作用的。IRF5与DNA具体的作用机理还在继续研究中。

【点评】
　发现IRF5作为转录阻遏物的新功能，协同其已知的转录激活物的作用共同调控巨噬细胞如何起作用。这增加了对机体免疫调节机制的认识。

【参考论文】Nature Immunology, 2011; DOI: 10.1038/ni.1990
IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses
Thomas Krausgruber, Katrina Blazek, Tim Smallie, et al.
Polymorphisms in the gene encoding the transcription factor IRF5 that lead to higher mRNA expression are associated with many autoimmune diseases. Here we show that IRF5 expression in macrophages was reversibly induced by inflammatory stimuli and contributed to the plasticity of macrophage polarization. High expression of IRF5 was characteristic of M1 macrophages, in which it directly activated transcription of the genes encoding interleukin 12 subunit p40 (IL-12p40), IL-12p35 and IL-23p19 and repressed the gene encoding IL-10. Consequently, those macrophages set up the environment for a potent T helper type 1 (TH1)-TH17 response. Global gene expression analysis demonstrated that exogenous IRF5 upregulated or downregulated expression of established phenotypic markers of M1 or M2 macrophages, respectively. Our data suggest a critical role for IRF5 in M1 macrophage polarization and define a previously unknown function for IRF5 as a transcriptional repressor.

4.  母体的干细胞解决胎儿细胞移植问题
【动态】  
母亲的干细胞很可能是出生前治疗遗传疾病的关键。美国加州大学的科学家通过一系列老鼠模型试验，确定是母亲的免疫反应阻止了胎儿接受移植的造血干细胞，而克服这一反应也很简单，就是移植来自母亲自身的干细胞。这样就提供了一种简单优质的解决方案使胎儿干细胞移植成为可达成的目标。第一次有了出生前治疗先天性干细胞障碍的可行策略。

【点评】
胎儿尚不具备的许多身体机能由母亲代劳，这是母体对胎儿的保护，也是对自身的保护。同时也体现了机体对组成部分包括孕育中的胎儿的统一调控。

【参考论文】Journal of Clinical Investigation, 2011; DOI: 10.1172/JCI44907
Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice
Amar Nijaga, Marta Wegorzewska, Erin Jarvis, et al.
Transplantation of allogeneic stem cells into the early gestational fetus, a treatment termed in utero hematopoietic cell transplantation (IUHCTx), could potentially overcome the limitations of bone marrow transplants, including graft rejection and the chronic immunosuppression required to prevent rejection. However, clinical use of IUHCTx has been hampered by poor engraftment, possibly due to a host immune response against the graft. Since the fetal immune system is relatively immature, we hypothesized that maternal cells trafficking into the fetus may pose the true barrier to effective IUHCTx. Here, we have demonstrated that there is macrochimerism of maternal leukocytes in the blood of unmanipulated mouse fetuses, with substantial increases in T cell trafficking after IUHCTx. To determine the contribution of these maternal lymphocytes to rejection after IUHCTx, we bred T and/or B cell–deficient mothers to wild-type fathers and performed allogeneic IUHCTx into the immunocompetent fetuses. There was a marked improvement in engraftment if the mother lacked T cells but not B cells, indicating that maternal T cells are the main barrier to engraftment. Furthermore, when the graft was matched to the mother, there was no difference in engraftment between syngeneic and allogeneic fetal recipients. Our study suggests that the clinical success of IUHCTx may be improved by transplanting cells matched to the mother.

5.  稀有癌症的独特基因型
【动态】
　美国约翰霍普金斯医学院的科学家的最新研究表明其肿瘤有特定基因编码错误的胰岛细胞癌患者存活时间是没有这类错误的患者的两倍。胰岛细胞癌占所有胰腺癌的大概5%，每个患有这种少见癌症的患者都有其独特的遗传编码能够预测疾病的侵袭性与其对特定治疗的敏感性。因此根据基因类型而不是只根据器官和细胞种类来划分癌症可能更有用。在这项新研究中，在MEN-1, DAXX 和 ATRX三个基因发生突变的胰岛细胞癌患者确诊后存活至少10年，而那些肿瘤没有这三个基因突变的患者超过60%死于确诊后5年内。

【点评】
通过基因分析根据某些确定联系来辅助诊断癌症或许有用，但是这些联系是否有因果关系需要仔细确认，不是真正癌症发病原因的就没有理由针对它开发治疗方法。

【参考论文】Science, 2011; DOI: 10.1126/science.1200609
DAXX/ATRX, MEN1, and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors
Y. Jiao, C. Shi, B. H. Edil, et al.
Pancreatic Neuroendocrine Tumors (PanNETs) are a rare but clinically important form of pancreatic neoplasia. To explore the genetic basis of PanNETs, we determined the exomic sequences of ten nonfamilial PanNETs and then screened the most commonly mutated genes in 58 additional PanNETs. The most frequently mutated genes specify proteins implicated in chromatin remodeling: 44% of the tumors had somatic inactivating mutations in MEN-1, which encodes menin, a component of a histone methyltransferase complex; and 43% had mutations in genes encoding either of the two subunits of a transcription/chromatin remodeling complex consisting of DAXX (death-domain associated protein) and ATRX (alpha thalassemia/mental retardation syndrome X-linked). Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. We also found mutations in genes in the mTOR (mammalian target of rapamycin) pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatment with mTOR inhibitors.

6. Ras效应物转换决定不同的细胞命运
【动态】
　美国国家癌症研究院估计去年美国有超过4万3000人诊断为胰腺癌，超过3万6000人死于胰腺癌。尽管遗传学进展表明Ras癌基因在几乎所有胰腺癌中都突变，但是信号通路网络的复杂性阻碍科学家找出潜在的治疗靶点。相对于人类有20多种可与Ras相互作用的下游搭档，蛔虫的此类相互作用关系就非常简单，因而成为退而求其次的研究目标以确定Ras如何选择搭档以及后续促进癌症的细胞发育中的关键事件。该研究确立了正常发育中Ras效应物的用途，可能会提供一种机理解释在效应物依赖和活化上细胞和癌症类型的差别。

【点评】
　以如此低等动物的研究结论做参考，研究人的问题，有时反而可能会误导，细胞命运的决定可能是诸多机制达成平衡的一个结果。

【参考论文】Developmental Cell, 2011; 20 (1): 84 DOI: 10.1016/j.devcel.2010.12.004
Ras Effector Switching Promotes Divergent Cell Fates in C. elegans Vulval Patterning
Tanya P. Zand, David J. Reiner, Channing J. Der.
The C. elegans vulva is patterned by epidermal growth factor (EGF) activation of Ras to control 1 fate, and 1 fate induces antagonistic Notch-dependent 2 fate. Furthermore, a spatial EGF gradient, in addition to inducing 1 fate, directly contributes to 2 fate via an unknown pathway. We find that in addition to its canonical effector, Raf, vulval Ras utilizes an exchange factor for the Ral small GTPase (RalGEF), such that Ras-RalGEF-Ral antagonizes Ras-Raf pro-1 fate activity. Consistent with its restricted expression pattern, Ral participates in EGF pro-2 activity. Thus, we have delineated a Ras effector-switching mechanism whereby position within the morphogen gradient dictates that Ras effector usage is switched to RalGEF from Raf to promote 2 instead of 1 fate. Our observations define the utility of Ras effector switching during normal development and may provide a possible mechanistic basis for cell and cancer-type differences in effector dependency and activation.