世界生命科学前沿动态周报（十九）

（08.09 --08.15 / 2010）
美宝国际集团:陶国新 

　　本周动态包括以下内容：沙门氏菌治疗肿瘤可诱发杀灭癌细胞免疫反应；脊髓损伤小鼠成功再生神经通路；发现骨髓中造血干细胞生态龛的重要成员；细胞因子介导的肿瘤免疫疗法；星形胶质细胞可转化为神经细胞。

1. 沙门氏菌治疗肿瘤可诱发杀灭癌细胞免疫反应
【摘要】美国科学促进会 2010-8-13 10:43:19
　　一项在小鼠中的新的研究报告说，用沙门氏菌治疗肿瘤可诱发一种能够有效杀灭癌细胞的免疫反应。该发现可帮助科学家们创制可注射到病人体内的杀灭肿瘤的免疫细胞，或其能证明对研发一种潜在的抗癌“疫苗”有所帮助。在体内巡查的免疫细胞常常可将早期的癌细胞识别为异常的细胞，并将其杀灭。这一过程依赖于连接蛋白43，这是可在不同类型的细胞间形成细小交通通道（称作间隙连接）的一种蛋白。被称作肽的肿瘤蛋白碎片可通过这些通道逃逸并进入到在其表面展示这些肽的免疫细胞之中。这些肽的作用相当于“红旗警示”，从而触发一种特异性的抗癌免疫反应。但是随着癌细胞的进展和增殖，它们可令免疫细胞无法对其进行识别。如今，Fabiana Saccheri及其在意大利的同事证明，将沙门氏菌注射到肿瘤之中可令这些肿瘤细胞重新能够被免疫细胞识别。研究人员发现，被注射的细菌发挥了一种关键性的功能：它们重新激活了连接蛋白43，而这种蛋白随着癌细胞的生长常常会受到抑制。在本研究中，该团队发现，来自小鼠和人的感染了沙门氏菌的黑色素瘤细胞可增加在这些细胞中的连接蛋白43的含量。 其结果是新的间隙连接形成了，它使得染有黄色荧光的小分子能够在肿瘤细胞之间通行或从肿瘤细胞进入免疫细胞。但是研究人员希望查明，这种可使肿瘤肽进入免疫细胞的间隙连接也会在活体动物中出现。因此，他们对患癌的小鼠进行了沙门氏菌的治疗并观察到，正如在实验室的分离细胞中所观察到的，这些肿瘤肽可通过间隙连接而进入到免疫细胞之中，它们在那里被装载到了细胞的表面。这些新被激活的免疫细胞突然能够识别并杀灭在小鼠中的肿瘤细胞。令人感兴趣的是，这种方法还保护小鼠不会发生癌症扩散到身体的其它部位，而这正是一种“疫苗接种”形式的预防性策略。
【点评】
　　通过细菌感染重新激活免疫细胞识别和杀灭肿瘤细胞，不失为一种富于想象力的手段，而能否有实用价值依然在于该方法有效性有多强以及使用时的安全性。即便不能发展成为一种高效的治疗癌症的方法，它还是提供了一种思路，即是否可能将难治性致命疾病通过非常规手段转变为容易处理的问题来解决。

【原文摘录】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. 脊髓损伤小鼠成功再生神经通路
【摘要】科技日报 2010-8-10 11:59:52
　　近期，研究人员首次诱导脊髓受损的小鼠再生出可控制自主行动的神经通路，这一成果有望开发出治疗瘫痪和其他运动功能性障碍的新方法。相关论文发表于《自然•神经科学》杂志。在对小鼠的研究中，美国加州大学欧文分校、加州大学圣地亚哥分校和哈佛大学联合组成的研究团队通过逆转一个分子通道中的生物钟而获得了这项突破，该分子通道对于皮质脊髓束神经通路而言非常关键。他们剔除了一种名为PTEN（同源性磷酸酶-张力蛋白）的酶，这种酶控制的分子通道叫做mTOR，是细胞生长的关键调节器。在发育初期，PTEN的活性很低，细胞增殖不受影响；当发育完成时，PTEN就会关闭，抑制mTOR分子通道，细胞也会失去任何再生能力。“在此之前，如此强大的神经再生不可能在脊髓中出现，”加州大学欧文分校里夫-欧文研究中心负责人、解剖学和神经生物学教授斯图尔特说，“瘫痪和因脊髓损伤导致的功能丧失一直被认为是无药可医的，但我们的研究发现指明了一种潜在的治疗方法，即诱导脊髓受伤患者体内的神经通路再生。”根据克里斯托弗和丹纳•利夫基金会提供的数据，大约有2%的美国人因脊髓损伤而出现某种形式的瘫痪，这主要是由于连接大脑和脊髓的神经通路中断导致的。一粒葡萄大小的损伤就可导致损伤面以下的功能全部丧失。比如，颈部的损伤可致胳膊和腿瘫痪，肩部以下感知全无，大小便失禁，性功能丧失，以及一系列次级健康风险，包括泌尿系统感染，由于无法移动双腿而生出褥疮和血栓等。斯图尔特说：“如果能够找到一个方法让这些遭到破坏的通路再生，所有这些丧失的功能都可以恢复。”他和同事们正在研究PTEN缺失疗法能否让脊髓损伤的小鼠恢复实际运动功能，并进一步了解最佳的治疗时间，同时试图为该疗法开发一套药物输送系统。
【点评】
　　通过剔除Pten基因，使脊髓神经细胞回到类似发育初期的状态从而恢复再生能力，修复损伤的神经通路。策略很好，只是目前还只在小鼠试验中观察到神经细胞的再生，能否恢复小鼠的实际运动功能不清楚。而且，如何实现体内脊髓神经细胞的Pten基因剔除或沉默是另一个巨大挑战。

【原文摘录】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. 发现骨髓中造血干细胞生态龛的重要成员
【摘要】
　　在骨髓中形成造血干细胞生态龛的细胞身份一直不清楚。现在，Paul Frenette及其同事识别出，表达巢蛋白nestin的间充质干细胞为形成生态龛的细胞。这些细胞与造血干细胞有密切物理关系，表达高水平的参与干细胞维护的基因，它们的删除会降低造血祖细胞的骨髓归巢功能。这项工作显示，骨髓中的干细胞生态龛是两种截然不同的体干细胞类型之间的一种伙伴关系。
【点评】
　　表达巢蛋白的间充质干细胞被发现在组成造血干细胞的生态龛和维护造血干细胞方面起重要作用。对于研究造血干细胞的生命规律和血液病的治疗上很可能有积极作用。

【原文摘录】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. 细胞因子介导的肿瘤免疫疗法
【摘要】
　　人体免疫系统成功地进化，能对付许多病原体。通过接种疫苗，我们能够驾驭和增进免疫反应来消灭传染病。尽管如此，我们还只是刚刚开始了解肿瘤自然免疫监视机制以及为什么有些情况下我们的免疫系统不能消除肿瘤的生长发育。本编综述回顾了最近在这一领域出现的鼓舞人心的研究结果和不断扩展的有关细胞因子诱导效应以及显示辅助细胞因子治疗很有希望促进抗肿瘤免疫的临床前和临床数据等方面的知识。
【点评】
　　提供给大家关于肿瘤免疫疗法的一些新进展和新希望。

【原文摘录】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. 星形胶质细胞可转化为神经细胞
【摘要】来源：《PLoS生物学》 发布时间：2010-8-11 9:34:09
　　德国慕尼黑大学、亥姆霍兹慕尼黑中心组成的一个研究小组18日宣布在脑细胞再生研究方面取得新进展：使用特殊的转录因子可使大脑皮层的星形胶质细胞转化为功能性神经细胞。这一成果将有助于老年痴呆症或中风等疾病的新疗法研究。由亥姆霍兹慕尼黑中心干细胞研究所所长玛格达莱娜•格茨领导的这个研究小组在最新一期美国《公共科学图书馆—生物学》杂志上报告说，通过研究证实，在大脑皮层的星形胶质细胞中植入“Neurogenin2”转录因子可使星形胶质细胞转变为兴奋性神经元，在同样的星形胶质细胞中植入“Dlx2”转录因子则可使其转变为抑制性神经元。
星形胶质细胞是哺乳动物脑内分布最广泛的一类细胞，其胞体发出的许多长而分支的突起伸展充填在神经细胞的胞体及其突起之间，起支持和分隔神经细胞的作用。德国研究人员指出，星形胶质细胞与放射状胶质细胞密切相关，而后者则是胎胚发育过程中大多数神经元的前驱细胞。德研究人员进一步解释说，格茨领导的研究小组在几年前的研究中已发现，在幼鼠大脑皮层本来不具有形成神经元能力的星形胶质细胞中植入特殊的调节蛋白，可促使其转变为神经元。而他们的最新研究则显示，新形成的神经元在特殊转录因子的影响下可进一步形成功能性突触，释放出兴奋性或抑制性的递质。不仅还在发育的星形胶质细胞发生转变，而且因受损而被激活的成熟大脑中的星形胶质细胞也能发生这种转变。这一发现使研究人员相信有望找到用脑中现有的星形胶质细胞“更新”因伤或疾病而受损的脑细胞的方法。（来源：新华社　班玮）
【点评】
通过基因技术直接改造和转变组织细胞类型的例子。对于体外再生神经细胞的研究有参考价值，但目前看不出有任何治疗上的实用价值。

【原文摘录】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.