世界生命科學前沿動態(tài)周報（四十）

【點評】
　盡管沒有使用iPS細胞，而是直接從皮膚細胞誘導形成的類軟骨細胞，在老鼠體內(nèi)還是有部分形成了腫瘤。這種使用僅知的少數(shù)誘導因子來變換細胞類別的方法目前還很難控制這一變化形成的是健康細胞。

【參考論文】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雙向調(diào)節(jié)免疫反應
【動態(tài)】
　　編碼提高mRNA表達的轉(zhuǎn)錄因子IRF5的基因多態(tài)性與許多自體免疫疾病相關。英國科學家最近發(fā)現(xiàn)IRF5蛋白在特定白細胞中起到“主開關”的作用，決定這些白細胞是促進還是抑制炎癥。炎癥反應是機體抵御象感染和組織損傷等有害刺激的重要手段，但是在很多情況下，過度發(fā)炎本身也會損害機體，像類風濕關節(jié)炎。免疫系統(tǒng)的巨噬細胞既能刺激發(fā)炎也能通過釋放化學信號改變其他細胞的行為來抑制炎癥。而本研究表明IRF5蛋白是決定巨噬細胞如何作用的分子開關。結果顯示在巨噬細胞中阻斷IRF5蛋白的產(chǎn)生可能會是一種治療一大群自體免疫疾病的有效方法。另外，提升IRF5蛋白水平可能有助于治療免疫系統(tǒng)功能低下。IRF5可能是通過激活那些刺激炎癥反應的基因和抑制相反功能的基因來起作用的。IRF5與DNA具體的作用機理還在繼續(xù)研究中。

【點評】
　發(fā)現(xiàn)IRF5作為轉(zhuǎn)錄阻遏物的新功能，協(xié)同其已知的轉(zhuǎn)錄激活物的作用共同調(diào)控巨噬細胞如何起作用。這增加了對機體免疫調(diào)節(jié)機制的認識。

【參考論文】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.  母體的干細胞解決胎兒細胞移植問題
【動態(tài)】  
母親的干細胞很可能是出生前治療遺傳疾病的關鍵。美國加州大學的科學家通過一系列老鼠模型試驗，確定是母親的免疫反應阻止了胎兒接受移植的造血干細胞，而克服這一反應也很簡單，就是移植來自母親自身的干細胞。這樣就提供了一種簡單優(yōu)質(zhì)的解決方案使胎兒干細胞移植成為可達成的目標。第一次有了出生前治療先天性干細胞障礙的可行策略。

【點評】
胎兒尚不具備的許多身體機能由母親代勞，這是母體對胎兒的保護，也是對自身的保護。同時也體現(xiàn)了機體對組成部分包括孕育中的胎兒的統(tǒng)一調(diào)控。

【參考論文】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.  稀有癌癥的獨特基因型
【動態(tài)】
　美國約翰霍普金斯醫(yī)學院的科學家的最新研究表明其腫瘤有特定基因編碼錯誤的胰島細胞癌患者存活時間是沒有這類錯誤的患者的兩倍。胰島細胞癌占所有胰腺癌的大概5%，每個患有這種少見癌癥的患者都有其獨特的遺傳編碼能夠預測疾病的侵襲性與其對特定治療的敏感性。因此根據(jù)基因類型而不是只根據(jù)器官和細胞種類來劃分癌癥可能更有用。在這項新研究中，在MEN-1, DAXX 和 ATRX三個基因發(fā)生突變的胰島細胞癌患者確診后存活至少10年，而那些腫瘤沒有這三個基因突變的患者超過60%死于確診后5年內(nèi)。

【點評】
通過基因分析根據(jù)某些確定聯(lián)系來輔助診斷癌癥或許有用，但是這些聯(lián)系是否有因果關系需要仔細確認，不是真正癌癥發(fā)病原因的就沒有理由針對它開發(fā)治療方法。

【參考論文】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效應物轉(zhuǎn)換決定不同的細胞命運
【動態(tài)】
　美國國家癌癥研究院估計去年美國有超過4萬3000人診斷為胰腺癌，超過3萬6000人死于胰腺癌。盡管遺傳學進展表明Ras癌基因在幾乎所有胰腺癌中都突變，但是信號通路網(wǎng)絡的復雜性阻礙科學家找出潛在的治療靶點。相對于人類有20多種可與Ras相互作用的下游搭檔，蛔蟲的此類相互作用關系就非常簡單，因而成為退而求其次的研究目標以確定Ras如何選擇搭檔以及后續(xù)促進癌癥的細胞發(fā)育中的關鍵事件。該研究確立了正常發(fā)育中Ras效應物的用途，可能會提供一種機理解釋在效應物依賴和活化上細胞和癌癥類型的差別。

【點評】
　以如此低等動物的研究結論做參考，研究人的問題，有時反而可能會誤導，細胞命運的決定可能是諸多機制達成平衡的一個結果。

【參考論文】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.