世界生命科學(xué)前沿動態(tài)周報（十九）

（08.09 --08.15 / 2010）
美寶國際集團(tuán):陶國新 

　　本周動態(tài)包括以下內(nèi)容：沙門氏菌治療腫瘤可誘發(fā)殺滅癌細(xì)胞免疫反應(yīng)；脊髓損傷小鼠成功再生神經(jīng)通路；發(fā)現(xiàn)骨髓中造血干細(xì)胞生態(tài)龕的重要成員；細(xì)胞因子介導(dǎo)的腫瘤免疫療法；星形膠質(zhì)細(xì)胞可轉(zhuǎn)化為神經(jīng)細(xì)胞。

1. 沙門氏菌治療腫瘤可誘發(fā)殺滅癌細(xì)胞免疫反應(yīng)
【摘要】美國科學(xué)促進(jìn)會 2010-8-13 10:43:19
　　一項在小鼠中的新的研究報告說，用沙門氏菌治療腫瘤可誘發(fā)一種能夠有效殺滅癌細(xì)胞的免疫反應(yīng)。該發(fā)現(xiàn)可幫助科學(xué)家們創(chuàng)制可注射到病人體內(nèi)的殺滅腫瘤的免疫細(xì)胞，或其能證明對研發(fā)一種潛在的抗癌“疫苗”有所幫助。在體內(nèi)巡查的免疫細(xì)胞常?？蓪⒃缙诘陌┘?xì)胞識別為異常的細(xì)胞，并將其殺滅。這一過程依賴于連接蛋白43，這是可在不同類型的細(xì)胞間形成細(xì)小交通通道（稱作間隙連接）的一種蛋白。被稱作肽的腫瘤蛋白碎片可通過這些通道逃逸并進(jìn)入到在其表面展示這些肽的免疫細(xì)胞之中。這些肽的作用相當(dāng)于“紅旗警示”，從而觸發(fā)一種特異性的抗癌免疫反應(yīng)。但是隨著癌細(xì)胞的進(jìn)展和增殖，它們可令免疫細(xì)胞無法對其進(jìn)行識別。如今，F(xiàn)abiana Saccheri及其在意大利的同事證明，將沙門氏菌注射到腫瘤之中可令這些腫瘤細(xì)胞重新能夠被免疫細(xì)胞識別。研究人員發(fā)現(xiàn)，被注射的細(xì)菌發(fā)揮了一種關(guān)鍵性的功能：它們重新激活了連接蛋白43，而這種蛋白隨著癌細(xì)胞的生長常常會受到抑制。在本研究中，該團(tuán)隊發(fā)現(xiàn)，來自小鼠和人的感染了沙門氏菌的黑色素瘤細(xì)胞可增加在這些細(xì)胞中的連接蛋白43的含量。 其結(jié)果是新的間隙連接形成了，它使得染有黃色熒光的小分子能夠在腫瘤細(xì)胞之間通行或從腫瘤細(xì)胞進(jìn)入免疫細(xì)胞。但是研究人員希望查明，這種可使腫瘤肽進(jìn)入免疫細(xì)胞的間隙連接也會在活體動物中出現(xiàn)。因此，他們對患癌的小鼠進(jìn)行了沙門氏菌的治療并觀察到，正如在實驗室的分離細(xì)胞中所觀察到的，這些腫瘤肽可通過間隙連接而進(jìn)入到免疫細(xì)胞之中，它們在那里被裝載到了細(xì)胞的表面。這些新被激活的免疫細(xì)胞突然能夠識別并殺滅在小鼠中的腫瘤細(xì)胞。令人感興趣的是，這種方法還保護(hù)小鼠不會發(fā)生癌癥擴(kuò)散到身體的其它部位，而這正是一種“疫苗接種”形式的預(yù)防性策略。
【點(diǎn)評】
　　通過細(xì)菌感染重新激活免疫細(xì)胞識別和殺滅腫瘤細(xì)胞，不失為一種富于想象力的手段，而能否有實用價值依然在于該方法有效性有多強(qiáng)以及使用時的安全性。即便不能發(fā)展成為一種高效的治療癌癥的方法，它還是提供了一種思路，即是否可能將難治性致命疾病通過非常規(guī)手段轉(zhuǎn)變?yōu)槿菀滋幚淼膯栴}來解決。

【原文摘錄】Sci. Transl. Med. 2, 44ra57 (2010). DOI: 10.1126/scitranslmed.3000739
Bacteria-induced gap junctions in tumors favor antigen cross-presentation and antitumor immunity
F. Saccheri, C. Pozzi, F. Avogadri, S. Barozzi, M. Faretta, P. Fusi, M. Rescigno.
Antigen-presenting dendritic cells (DCs) trigger the activation of cytotoxic CD8 T cells that target and eliminate cells with the antigen on their surface. Although DCs usually pick up and process antigens themselves, they can also receive peptide antigens from other cells via gap junctions. We demonstrate here that infection with Salmonella can induce, in both human and murine melanoma cells, the up-regulation of connexin 43 (Cx43), a ubiquitous protein that forms gap junctions and that is normally lost during melanoma progression. Bacteria-treated melanoma cells can establish functional gap junctions with adjacent DCs. After bacterial infection, these gap junctions transferred preprocessed antigenic peptides from the tumor cells to the DCs, which then presented those peptides on their surface. These peptides activated cytotoxic T cells against the tumor antigen, which could control the growth of distant uninfected tumors. Melanoma cells in which Cx43 had been silenced, when infected in vivo with bacteria, failed to elicit a cytotoxic antitumor response, indicating that this Cx43 mechanism is the principal one used in vivo for the generation of antitumor responses. The Cx43-dependent cross-presentation pathway is more effective than standard protocols of DC loading (peptide, tumor lysates, or apoptotic bodies) for generating DC-based tumor vaccines that both inhibit existing tumors and prevent tumor establishment. In conclusion, we exploited an antimicrobial response present in tumor cells to activate cytotoxic CD8 T cells specific for tumor-generated peptides that could directly recognize and kill tumor cells.

2. 脊髓損傷小鼠成功再生神經(jīng)通路
【摘要】科技日報 2010-8-10 11:59:52
　　近期，研究人員首次誘導(dǎo)脊髓受損的小鼠再生出可控制自主行動的神經(jīng)通路，這一成果有望開發(fā)出治療癱瘓和其他運(yùn)動功能性障礙的新方法。相關(guān)論文發(fā)表于《自然•神經(jīng)科學(xué)》雜志。在對小鼠的研究中，美國加州大學(xué)歐文分校、加州大學(xué)圣地亞哥分校和哈佛大學(xué)聯(lián)合組成的研究團(tuán)隊通過逆轉(zhuǎn)一個分子通道中的生物鐘而獲得了這項突破，該分子通道對于皮質(zhì)脊髓束神經(jīng)通路而言非常關(guān)鍵。他們剔除了一種名為PTEN（同源性磷酸酶-張力蛋白）的酶，這種酶控制的分子通道叫做mTOR，是細(xì)胞生長的關(guān)鍵調(diào)節(jié)器。在發(fā)育初期，PTEN的活性很低，細(xì)胞增殖不受影響；當(dāng)發(fā)育完成時，PTEN就會關(guān)閉，抑制mTOR分子通道，細(xì)胞也會失去任何再生能力。“在此之前，如此強(qiáng)大的神經(jīng)再生不可能在脊髓中出現(xiàn)，”加州大學(xué)歐文分校里夫-歐文研究中心負(fù)責(zé)人、解剖學(xué)和神經(jīng)生物學(xué)教授斯圖爾特說，“癱瘓和因脊髓損傷導(dǎo)致的功能喪失一直被認(rèn)為是無藥可醫(yī)的，但我們的研究發(fā)現(xiàn)指明了一種潛在的治療方法，即誘導(dǎo)脊髓受傷患者體內(nèi)的神經(jīng)通路再生?！备鶕?jù)克里斯托弗和丹納•利夫基金會提供的數(shù)據(jù)，大約有2%的美國人因脊髓損傷而出現(xiàn)某種形式的癱瘓，這主要是由于連接大腦和脊髓的神經(jīng)通路中斷導(dǎo)致的。一粒葡萄大小的損傷就可導(dǎo)致?lián)p傷面以下的功能全部喪失。比如，頸部的損傷可致胳膊和腿癱瘓，肩部以下感知全無，大小便失禁，性功能喪失，以及一系列次級健康風(fēng)險，包括泌尿系統(tǒng)感染，由于無法移動雙腿而生出褥瘡和血栓等。斯圖爾特說：“如果能夠找到一個方法讓這些遭到破壞的通路再生，所有這些喪失的功能都可以恢復(fù)?！彼屯聜冋谘芯縋TEN缺失療法能否讓脊髓損傷的小鼠恢復(fù)實際運(yùn)動功能，并進(jìn)一步了解最佳的治療時間，同時試圖為該療法開發(fā)一套藥物輸送系統(tǒng)。
【點(diǎn)評】
　　通過剔除Pten基因，使脊髓神經(jīng)細(xì)胞回到類似發(fā)育初期的狀態(tài)從而恢復(fù)再生能力，修復(fù)損傷的神經(jīng)通路。策略很好，只是目前還只在小鼠試驗中觀察到神經(jīng)細(xì)胞的再生，能否恢復(fù)小鼠的實際運(yùn)動功能不清楚。而且，如何實現(xiàn)體內(nèi)脊髓神經(jīng)細(xì)胞的Pten基因剔除或沉默是另一個巨大挑戰(zhàn)。

【原文摘錄】Nature Neuroscience doi:10.1038/nn.2603
PTEN deletion enhances the regenerative ability of adult corticospinal neurons
Kai Liu,Yi Lu,Jae K Lee, et al.
Despite the essential role of the corticospinal tract (CST) in controlling voluntary movements, successful regeneration of large numbers of injured CST axons beyond a spinal cord lesion has never been achieved. We found that PTEN/mTOR are critical for controlling the regenerative capacity of mouse corticospinal neurons. After development, the regrowth potential of CST axons was lost and this was accompanied by a downregulation of mTOR activity in corticospinal neurons. Axonal injury further diminished neuronal mTOR activity in these neurons. Forced upregulation of mTOR activity in corticospinal neurons by conditional deletion of Pten, a negative regulator of mTOR, enhanced compensatory sprouting of uninjured CST axons and enabled successful regeneration of a cohort of injured CST axons past a spinal cord lesion. Furthermore, these regenerating CST axons possessed the ability to reform synapses in spinal segments distal to the injury. Thus, modulating neuronal intrinsic PTEN/mTOR activity represents a potential therapeutic strategy for promoting axon regeneration and functional repair after adult spinal cord injury.

3. 發(fā)現(xiàn)骨髓中造血干細(xì)胞生態(tài)龕的重要成員
【摘要】
　　在骨髓中形成造血干細(xì)胞生態(tài)龕的細(xì)胞身份一直不清楚。現(xiàn)在，Paul Frenette及其同事識別出，表達(dá)巢蛋白nestin的間充質(zhì)干細(xì)胞為形成生態(tài)龕的細(xì)胞。這些細(xì)胞與造血干細(xì)胞有密切物理關(guān)系，表達(dá)高水平的參與干細(xì)胞維護(hù)的基因，它們的刪除會降低造血祖細(xì)胞的骨髓歸巢功能。這項工作顯示，骨髓中的干細(xì)胞生態(tài)龕是兩種截然不同的體干細(xì)胞類型之間的一種伙伴關(guān)系。
【點(diǎn)評】
　　表達(dá)巢蛋白的間充質(zhì)干細(xì)胞被發(fā)現(xiàn)在組成造血干細(xì)胞的生態(tài)龕和維護(hù)造血干細(xì)胞方面起重要作用。對于研究造血干細(xì)胞的生命規(guī)律和血液病的治療上很可能有積極作用。

【原文摘錄】Nature 466, 829-834 (12 August 2010) | doi:10.1038/nature09262
Mesenchymal and haematopoietic stem cells form a unique bone marrow niche
Simón Méndez-Ferrer, Tatyana V. Michurina, Francesca Ferraro, et al.
The cellular constituents forming the haematopoietic stem cell (HSC) niche in the bone marrow are unclear, with studies implicating osteoblasts, endothelial and perivascular cells. Here we demonstrate that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component. Nestin+ MSCs contain all the bone-marrow colony-forming-unit fibroblastic activity and can be propagated as non-adherent ‘mesenspheres’ that can self-renew and expand in serial transplantations. Nestin+ MSCs are spatially associated with HSCs and adrenergic nerve fibres, and highly express HSC maintenance genes. These genes, and others triggering osteoblastic differentiation, are selectively downregulated during enforced HSC mobilization or β3 adrenoreceptor activation. Whereas parathormone administration doubles the number of bone marrow nestin+ cells and favours their osteoblastic differentiation, in vivo nestin+ cell depletion rapidly reduces HSC content in the bone marrow. Purified HSCs home near nestin+ MSCs in the bone marrow of lethally irradiated mice, whereas in vivo nestin+ cell depletion significantly reduces bone marrow homing of haematopoietic progenitors. These results uncover an unprecedented partnership between two distinct somatic stem-cell types and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs.

4. 細(xì)胞因子介導(dǎo)的腫瘤免疫療法
【摘要】
　　人體免疫系統(tǒng)成功地進(jìn)化，能對付許多病原體。通過接種疫苗，我們能夠駕馭和增進(jìn)免疫反應(yīng)來消滅傳染病。盡管如此，我們還只是剛剛開始了解腫瘤自然免疫監(jiān)視機(jī)制以及為什么有些情況下我們的免疫系統(tǒng)不能消除腫瘤的生長發(fā)育。本編綜述回顧了最近在這一領(lǐng)域出現(xiàn)的鼓舞人心的研究結(jié)果和不斷擴(kuò)展的有關(guān)細(xì)胞因子誘導(dǎo)效應(yīng)以及顯示輔助細(xì)胞因子治療很有希望促進(jìn)抗腫瘤免疫的臨床前和臨床數(shù)據(jù)等方面的知識。
【點(diǎn)評】
　　提供給大家關(guān)于腫瘤免疫療法的一些新進(jìn)展和新希望。

【原文摘錄】Trends in Pharmacological Sciences, Volume 31, Issue 8, 356-363
Fighting cancers from within: augmenting tumor immunity with cytokine therapy
Marc Pellegrini, Tak W. Mak, Pamela S. Ohashi
The human immune system has successfully evolved to fight many pathogens. Through vaccination, we can harness and improve immune responses to eradicate infections. Despite this success, we are only now beginning to understand the natural tumor immune surveillance mechanisms and why, in some instances, our immune system fails to abrogate the development and growth of tumors. Encouraging results with the latest immunotherapies have renewed enthusiasm in the field. A central component of these therapies is the contribution of cytokines. Here we review our expanding knowledge of cytokine-induced effects as well as preclinical and clinical data that indicate adjuvant cytokine therapies may hold much promise in improving anti-tumor immunity. Further studies on optimal synergistic combinations, timing, duration and additional adjuvant therapies are required to realize the full potential of cytokines as immunotherapeutic agents.

5. 星形膠質(zhì)細(xì)胞可轉(zhuǎn)化為神經(jīng)細(xì)胞
【摘要】來源：《PLoS生物學(xué)》 發(fā)布時間：2010-8-11 9:34:09
　　德國慕尼黑大學(xué)、亥姆霍茲慕尼黑中心組成的一個研究小組18日宣布在腦細(xì)胞再生研究方面取得新進(jìn)展：使用特殊的轉(zhuǎn)錄因子可使大腦皮層的星形膠質(zhì)細(xì)胞轉(zhuǎn)化為功能性神經(jīng)細(xì)胞。這一成果將有助于老年癡呆癥或中風(fēng)等疾病的新療法研究。由亥姆霍茲慕尼黑中心干細(xì)胞研究所所長瑪格達(dá)萊娜•格茨領(lǐng)導(dǎo)的這個研究小組在最新一期美國《公共科學(xué)圖書館—生物學(xué)》雜志上報告說，通過研究證實，在大腦皮層的星形膠質(zhì)細(xì)胞中植入“Neurogenin2”轉(zhuǎn)錄因子可使星形膠質(zhì)細(xì)胞轉(zhuǎn)變?yōu)榕d奮性神經(jīng)元，在同樣的星形膠質(zhì)細(xì)胞中植入“Dlx2”轉(zhuǎn)錄因子則可使其轉(zhuǎn)變?yōu)橐种菩陨窠?jīng)元。
星形膠質(zhì)細(xì)胞是哺乳動物腦內(nèi)分布最廣泛的一類細(xì)胞，其胞體發(fā)出的許多長而分支的突起伸展充填在神經(jīng)細(xì)胞的胞體及其突起之間，起支持和分隔神經(jīng)細(xì)胞的作用。德國研究人員指出，星形膠質(zhì)細(xì)胞與放射狀膠質(zhì)細(xì)胞密切相關(guān)，而后者則是胎胚發(fā)育過程中大多數(shù)神經(jīng)元的前驅(qū)細(xì)胞。德研究人員進(jìn)一步解釋說，格茨領(lǐng)導(dǎo)的研究小組在幾年前的研究中已發(fā)現(xiàn)，在幼鼠大腦皮層本來不具有形成神經(jīng)元能力的星形膠質(zhì)細(xì)胞中植入特殊的調(diào)節(jié)蛋白，可促使其轉(zhuǎn)變?yōu)樯窠?jīng)元。而他們的最新研究則顯示，新形成的神經(jīng)元在特殊轉(zhuǎn)錄因子的影響下可進(jìn)一步形成功能性突觸，釋放出興奮性或抑制性的遞質(zhì)。不僅還在發(fā)育的星形膠質(zhì)細(xì)胞發(fā)生轉(zhuǎn)變，而且因受損而被激活的成熟大腦中的星形膠質(zhì)細(xì)胞也能發(fā)生這種轉(zhuǎn)變。這一發(fā)現(xiàn)使研究人員相信有望找到用腦中現(xiàn)有的星形膠質(zhì)細(xì)胞“更新”因傷或疾病而受損的腦細(xì)胞的方法。（來源：新華社　班瑋）
【點(diǎn)評】
通過基因技術(shù)直接改造和轉(zhuǎn)變組織細(xì)胞類型的例子。對于體外再生神經(jīng)細(xì)胞的研究有參考價值，但目前看不出有任何治療上的實用價值。

【原文摘錄】PLoS Biol 8(5): e1000373. doi:10.1371/journal.pbio.1000373
Directing Astroglia from the Cerebral Cortex into Subtype Specific Functional Neurons.
Heinrich C, Blum R, Gascón S, et al.
Astroglia from the postnatal cerebral cortex can be reprogrammed in vitro to generate neurons following forced expression of neurogenic transcription factors, thus opening new avenues towards a potential use of endogenous astroglia for brain repair. However, in previous attempts astroglia-derived neurons failed to establish functional synapses, a severe limitation towards functional neurogenesis. It remained therefore also unknown whether neurons derived from reprogrammed astroglia could be directed towards distinct neuronal subtype identities by selective expression of distinct neurogenic fate determinants. Here we show that strong and persistent expression of neurogenic fate determinants driven by silencing-resistant retroviral vectors instructs astroglia from the postnatal cortex in vitro to mature into fully functional, synapse-forming neurons. Importantly, the neurotransmitter fate choice of astroglia-derived neurons can be controlled by selective expression of distinct neurogenic transcription factors: forced expression of the dorsal telencephalic fate determinant neurogenin-2 (Neurog2) directs cortical astroglia to generate synapse-forming glutamatergic neurons; in contrast, the ventral telencephalic fate determinant Dlx2 induces a GABAergic identity, although the overall efficiency of Dlx2-mediated neuronal reprogramming is much lower compared to Neurog2, suggesting that cortical astroglia possess a higher competence to respond to the dorsal telencephalic fate determinant. Interestingly, however, reprogramming of astroglia towards the generation of GABAergic neurons was greatly facilitated when the astroglial cells were first expanded as neurosphere cells prior to transduction with Dlx2. Importantly, this approach of expansion under neurosphere conditions and subsequent reprogramming with distinct neurogenic transcription factors can also be extended to reactive astroglia isolated from the adult injured cerebral cortex, allowing for the selective generation of glutamatergic or GABAergic neurons. These data provide evidence that cortical astroglia can undergo a conversion across cell lineages by forced expression of a single neurogenic transcription factor, stably generating fully differentiated neurons. Moreover, neuronal reprogramming of astroglia is not restricted to postnatal stages but can also be achieved from terminally differentiated astroglia of the adult cerebral cortex following injury-induced reactivation.