世界生命科學(xué)前沿動態(tài)周報（四十五）

【點評】
胰腺β細(xì)胞轉(zhuǎn)變?yōu)棣良?xì)胞的機(jī)制說明DNA甲基化等表觀調(diào)控是決定細(xì)胞生命屬性的重要因素，單只DNA本身并不能決定細(xì)胞的生命屬性。這也為合理調(diào)節(jié)表觀調(diào)控以影響細(xì)胞生命屬性提供了科學(xué)依據(jù)。

【參考論文】Developmental Cell, 2011; 20 (4): 419 DOI:10.1016/j.devcel.2011.03.012
Pancreatic β Cell Identity Is Maintained by DNA Methylation-Mediated Repression of Arx
Sangeeta Dhawan, Senta Georgia, Shuen-ing Tschen, Guoping Fan, Anil Bhushan
Adult pancreatic β cells can replicate during growth and after injury to maintain glucose homeostasis. Here, we report that β cells deficient in Dnmt1, an enzyme that propagates DNA methylation patterns during cell division, were converted to α cells. We identified the lineage determination gene aristaless-related homeobox (Arx), as methylated and repressed in β cells, and hypomethylated and expressed in α cells and Dnmt1-deficient β cells. We show that the methylated region of the Arx locus in β cells was bound by methyl-binding protein MeCP2, which recruited PRMT6, an enzyme that methylates histone H3R2 resulting in repression of Arx. This suggests that propagation of DNA methylation during cell division also ensures recruitment of enzymatic machinery capable of modifying and transmitting histone marks. Our results reveal that propagation of DNA methylation during cell division is essential for repression of α cell lineage determination genes to maintain pancreatic β cell identity.

3.通過激活成熟神經(jīng)元中的BMP/Smad1信號通路再生受傷脊椎中的軸突神經(jīng)
【動態(tài)】
　　軸突生長潛力在年輕神經(jīng)元中最高但隨年齡增長而消失，因而成為成體受傷后軸突再生的顯著障礙。一項新研究表明在DRG神經(jīng)元中Smad1依賴的骨成型蛋白（BMP）逐步被調(diào)節(jié)控制軸突生長。下調(diào)該途徑造成年齡相關(guān)的軸突生長潛力的下降。在成熟的DRG神經(jīng)元中選擇性重新激活Smad1導(dǎo)致脊椎損傷的老鼠模型感覺神經(jīng)再生。Smad1信號可以通過臨床適用的最小侵入技術(shù)運送編碼BMP4的AAV載體來有效的操控。重要的是，即使是脊椎損傷后實施AAV治療，斷了的軸突也能再生，因此很像相應(yīng)的臨床事件。

【點評】
　 這一神經(jīng)再生的研究也說明DNA并非決定細(xì)胞生命活動的關(guān)鍵，對基因表達(dá)的調(diào)控更重要。

【參考論文】PNAS 2011, doi: 10.1073/pnas.1100426108
Regeneration of axons in injured spinal cord by activation of bone morphogenetic protein/Smad1 signaling pathway in adult neurons
Pranav Parikha, Yuhan Haoa, Mohsen Hosseinkhania.
Axon growth potential is highest in young neurons but diminishes with age, thus becoming a significant obstacle to axonal regeneration after injury in maturity. The mechanism for the decline is incompletely understood, and no effective clinical treatment is available to rekindle innate growth capability. Here, we show that Smad1-dependent bone morphogenetic protein (BMP) signaling is developmentally regulated and governs axonal growth in dorsal root ganglion (DRG) neurons. Down-regulation of the pathway contributes to the age-related decline of the axon growth potential. Reactivating Smad1 selectively in adult DRG neurons results in sensory axon regeneration in a mouse model of spinal cord injury (SCI). Smad1 signaling can be effectively manipulated by an adeno-associated virus (AAV) vector encoding BMP4 delivered by a clinically applicable and minimally invasive technique, an approach devoid of unwanted abnormalities in mechanosensation or pain perception. Importantly, transected axons are able to regenerate even when the AAV treatment is delivered after SCI, thus mimicking a clinically relevant scenario. Together, our results identify a therapeutic target to promote axonal regeneration after SCI.

4.  線粒體作治療癌癥的靶點
【動態(tài)】  
有關(guān)癌細(xì)胞線粒體的一些研究引導(dǎo)了發(fā)展針對線粒體蛋白和功能的無遺傳毒性的抗癌療法。目前已經(jīng)明確的線粒體在細(xì)胞凋亡中的作用提供了腫瘤細(xì)胞自殺的新靶點。線粒體的作用是作為對細(xì)胞壓力和損傷做出反應(yīng)的中央轉(zhuǎn)換器?？梢葬槍Π┘?xì)胞中導(dǎo)致免于凋亡的那些變化來抑制其增殖。因為癌細(xì)胞代謝的重組涉及到增加糖酵解，看起來通過針對HIF-1 或HIF-1基因編碼的代謝酶來阻斷InsP3R Ca2+的釋放或響應(yīng)缺氧的適應(yīng)性途徑代表了一種可行的癌癥治療方法。在體外向癌細(xì)胞添加白藜蘆醇后很快發(fā)生的是細(xì)胞內(nèi)數(shù)秒內(nèi)即可測到的Ca2+的增多。在添加無毒的類黃酮時也觀察到Ca2+的釋放，看來值得找出鈣活化中涉及的模型化合物白藜蘆醇的作用靶點。

【點評】
針對癌細(xì)胞線粒體與正常細(xì)胞線粒體的差異進(jìn)行癌癥治療的思路是對的,但是目前這種差異的細(xì)節(jié)還不是很清楚。

【參考論文】Journal of cellular physiology. 2011 DOI 10.1002/jcp.22788
Targeting mitochondria as a therapeutic target in cancer
Wenner CE
Knowledge of re-programming in cancer cells with metabolic differences from their normal counterparts has resulted in new examination of therapeutic approaches. Several studies of the role of tumor mitochondria in cancer have led to the development of non-genotoxic therapies which target mitochondrial proteins, function. The now well-established functions of mitochondria in apoptosis provide novel targets for tumor cell suicide. Mitochondria serve as a central hub for responses to cellular stress as well as injury. The alterations in cancer cells which result in protection from apoptosis can be targeted to inhibit proliferation. Because of the reprogramming of cancer cell metabolism involving increased glycolysis, it appears that blocking InsP3R Ca2+ release or adaptive pathways in response to hypoxia by targeting HIF-1 or metabolic enzymes encoded by the HIF-1 gene represents a feasible therapeutic approach to cancer. A very early in vitro event found in tumor cells following resveratrol addition is an increase in intracellular Ca2+, measurable within seconds. Ca2+ release is also observed with non-toxic flavonoids and a goal to identify the sentinel targets of resveratrol as a model compound involved in calcium activation seems worthwhile. New findings of the relationship between autophagy and apoptosis are discussed. The contribution of ROS generated by mitochondria is also considered. New data as to how cyclophilins and VDAC are involved in mitochondrial hexokinase protection of factors that induce apoptosis are reviewed. In addition, chemotherapeutic approaches based on Aktactivated mTORC1 are described, and their relationship to the role of aerobic glycolysis in this protection.

5.  小分子協(xié)同作用維持人體胚胎干細(xì)胞早期分化后的長期穩(wěn)定自我更新
【動態(tài)】
    小分子抑制劑迅速誘導(dǎo)人體胚胎干細(xì)胞轉(zhuǎn)變?yōu)樵忌窠?jīng)祖細(xì)胞并維持長期自我更新。人體胚胎干細(xì)胞賦予了再生醫(yī)學(xué)巨大希望。通常人體胚胎干細(xì)胞的應(yīng)用需要其在體外分化成期望的均一細(xì)胞群。目前的人體胚胎干細(xì)胞分化模式面臨的一個主要挑戰(zhàn)是不能有效鎖定并長期穩(wěn)定擴(kuò)增那些保有廣泛的分化能力，更重要的是發(fā)育階段特異性的分化傾向的原始的細(xì)胞系特異性干細(xì)胞/祖細(xì)胞群。一項新的研究報告了用小分子協(xié)同抑制糖原合成酶激酶3（GSK3）,轉(zhuǎn)化生長因子β (TGF-β)，和Notch信號途徑能夠在特定化學(xué)條件下于一周內(nèi)有效的將單層培養(yǎng)的人體胚胎干細(xì)胞轉(zhuǎn)變成均一的原始神經(jīng)上皮細(xì)胞。這些原始神經(jīng)上皮能夠在白細(xì)胞抑制因子，GSK3抑制劑（CHIR99021）和TGF-β受體抑制劑（SB431542）存在的情況下穩(wěn)定的自我更新；保持高潛力的神經(jīng)生長能力和對中腦后腦神經(jīng)亞型引導(dǎo)性神經(jīng)模式線索的反應(yīng)性；并表現(xiàn)出體內(nèi)的整體性。

【點評】
通過小分子抑制劑協(xié)同作用調(diào)控不同的信號途徑，來達(dá)到阻止干細(xì)胞進(jìn)一步分化和維持干細(xì)胞長期穩(wěn)定擴(kuò)增，對于干細(xì)胞體外培養(yǎng)還是有些價值的，只是這種人為規(guī)定的環(huán)境下培育的干細(xì)胞能否發(fā)揮體內(nèi)正常生理條件下的干細(xì)胞功能還有很大疑問。

【參考論文】PNAS 2011 ; doi:10.1073/pnas.1014041108
Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by small molecule inhibitors
Wenlin Li, Woong Sun, Yu Zhang, et al.
Human embryonic stem cells (hESCs) hold enormous promise for regenerative medicine. Typically, hESC-based applications would require their in vitro differentiation into a desirable homogenous cell population. A major challenge of the current hESC differentiation paradigm is the inability to effectively capture and, in the long-term, stably expand primitive lineage-specific stem/precursor cells that retain broad differentiation potential and, more importantly, developmental stage-specific differentiation propensity. Here, we report synergistic inhibition of glycogen synthase kinase 3 (GSK3), transforming growth factor β (TGF-β), and Notch signaling pathways by small molecules can efficiently convert monolayer cultured hESCs into homogenous primitive neuroepithelium within 1 wk under chemically defined condition. These primitive neuroepithelia can stably self-renew in the presence of leukemia inhibitory factor, GSK3 inhibitor (CHIR99021), and TGF-β receptor inhibitor (SB431542); retain high neurogenic potential and responsiveness to instructive neural patterning cues toward midbrain and hindbrain neuronal subtypes; and exhibit in vivo integration. Our work uniformly captures and maintains primitive neural stem cells from hESCs.

6.  鑒別出與肌肉修復(fù)有關(guān)的關(guān)鍵基因
【動態(tài)】
    作為胚胎骨骼肌發(fā)育的關(guān)鍵，衛(wèi)星細(xì)胞（SCs）直至嬰兒期還在繼續(xù)活躍的增加肌肉質(zhì)量。之后，他們數(shù)量逐漸減少并沉寂下來，直到損傷或退化激活它們增殖。衛(wèi)星細(xì)胞維持肌肉生長并使成熟的骨骼肌具有強(qiáng)大的再生能力。一項新的研究報告了Polycomb抑制性復(fù)合物2（PRC2）的酶亞基EZH2，在Pax7+/Myf5− 干細(xì)胞和 Pax7+/Myf5+ 肌原性前體細(xì)胞中都有表達(dá)，并且是保持衛(wèi)星細(xì)胞池穩(wěn)定所需要的。有條件的切除SCs的Ezh2的老鼠出生后Pax7+細(xì)胞很少且肌肉數(shù)量下降還不能適當(dāng)再生。這些缺陷與受損的SC增殖及非肌細(xì)胞中表達(dá)的基因的去抑制有聯(lián)系。因此，EZH2在SCs中控制自我更新和增殖以及維持合適的轉(zhuǎn)錄程序。

【點評】
該研究對衛(wèi)星細(xì)胞的增殖規(guī)律以及肌肉損傷后修復(fù)有了更深入的了解，有助于損傷和衰老肌肉復(fù)原的研究。