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天下生命科学前沿动态周报（十九）
（08.09 --08.15 / 2010）
一竞技国际集团: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 ；脊髓损伤小鼠乐成再生神经通路 ；发明骨髓中造血干细胞生态龛的主要成员 ；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】美国科学增进会 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用杀灭癌细胞的免疫反应。该发明可资助科学家们创造可注射到病人体内的杀灭肿瘤的免疫细胞，或其能证实对研发一种潜在的抗癌“疫苗”有所资助。在体内巡查的免疫细胞常�？山缙诘陌┫赴侗鹞斐５南赴�，并将其杀灭。这一历程依赖于毗连卵白43，这是可在差别类型的细胞间形成细小交通通道（称作间隙毗连）的一种卵白。被称作肽的肿瘤卵白碎片可通过这些通道逃逸并进入到在其外貌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。可是随着癌细胞的希望和增殖，它们可令免疫细胞无法对其举行识别。现在，Fabiana Saccheri及其在意大利的同事证实，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。研究职员发明，被注射的细菌施展了一种要害性的功效：它们重新激活了毗连卵白43，而这种卵白随着癌细胞的生长常� ；崾艿揭种�。在本研究中，该团队发明，来自小鼠和人的熏染了沙门氏菌的玄色素瘤细胞可增添在这些细胞中的毗连卵白43的含量。 其效果是新的间隙毗连形成了，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。可是研究职员希望查明，这种可使肿瘤肽进入免疫细胞的间隙毗连也会在活体动物中泛起。因此，他们对患癌的小鼠举行了沙门氏菌的治疗并视察到，正如在实验室的疏散细胞中所视察到的，这些肿瘤肽可通过间隙毗连而进入到免疫细胞之中，它们在那里被装载到了细胞的外貌。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，这种要领还� ；ば∈蟛换岜┲⒗┥⒌缴硖宓钠渌课�，而这正是一种“疫苗接种”形式的预防性战略。
【点评】
通详尽菌熏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，而能否有适用价值依然在于该要领有用性有多强以及使用时的清静性。即便不可生长成为一种高效的治疗癌症的要领，它照旧提供了一种思绪，即是否可能将难治性致命疾病通过非通例手段转变为容易处置惩罚的问题来解决。
【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. 脊髓损伤小鼠乐成再生神经通路
【摘要】科技日报 2010-8-10 11:59:52
近期，研究职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，这一效果有望开发出治疗瘫痪和其他运动功效性障碍的新要领。相关论文揭晓于《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团结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，该分子通道关于皮质脊髓束神经通路而言很是要害。他们剔除了一种名为PTEN（同源性磷酸酶-张力卵白）的酶，这种酶控制的分子通道叫做mTOR，是细胞生长的要害调理器。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，云云强盛的神经再生不可能在脊髓中泛起，”加州大学欧文分校里夫-欧文研究中心认真人、剖解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效损失一直被以为是无药可医的，但我们的研究发明指明晰一种潜在的治疗要领，即诱导脊髓受伤患者体内的神经通路再生。”凭证克里斯托弗和丹纳•利夫基金会提供的数据，约莫有2%的美国人因脊髓损伤而泛起某种形式的瘫痪，这主要是由于毗连大脑和脊髓的神经通路中止导致的。一粒葡萄巨细的损伤就可导致损伤面以下的功效所有损失。好比，颈部的损伤可致胳膊和腿瘫痪，肩部以下感知全无，巨细便失禁，性功效损失，以及一系列次级康健危害，包括泌尿系统熏染，由于无法移动双腿而生出褥疮和血栓等。斯图尔特说：“若是能够找到一个要领让这些遭到破损的通路再生，所有这些损失的功效都可以恢复。”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现实运动功效，并进一步相识最佳的治疗时间，同时试图为该疗法开发一套药物运送系统。
【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。战略很好，只是现在还只在小鼠试验中视察到神经细胞的再生，能否恢复小鼠的现实运动功效不清晰。并且，怎样实现体内脊髓神经细胞的Pten基因剔除或默然是另一个重大挑战。
【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. 发明骨髓中造血干细胞生态龛的主要成员
【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晰。现在，Paul Frenette及其同事识别出，表达巢卵白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亲近物理关系，表达高水平的加入干细胞维护的基因，它们的删除会降低造血祖细胞的骨髓归巢功效。这项事情显示，骨髓中的干细胞生态龛是两种截然差别的体干细胞类型之间的一种伙伴关系。
【点评】
表达巢卵白的间充质干细胞被发明在组成造血干细胞的生态龛和维护造血干细胞方面起主要作用。关于研究造血干细胞的生命纪律和血液病的治疗上很可能有起劲作用。
【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】
人体免疫系统乐成地进化，能搪塞许多病原体。通过接种疫苗，我们能够驾驭和增进免疫反应来祛除熏染病。只管云云，我们还只是刚刚最先相识肿瘤自然免疫监视机制以及为什么有些情形下我们的免疫系统不可消除肿瘤的生长发育。本编综述回首了最近在这一领域泛起的鼓舞人心的研究效果和一直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增进抗肿瘤免疫的临床前和临床数据等方面的知识。
【点评】
提供应各人关于肿瘤免疫疗法的一些新希望和新希望。
【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】泉源：《PLoS生物学》 宣布时间：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希望：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效性神经细胞。这一效果将有助于晚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•格茨向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漫衍最普遍的一类细胞，其胞体发出的许多长而分支的突起舒展充填在神经细胞的胞体及其突起之间，起支持和脱离神经细胞的作用。德国研究职员指出，星形胶质细胞与放射状胶质细胞亲近相关，此后者则是胎胚发育历程中大大都神经元的前驱细胞。德研究职员进一步诠释说，格茨向导的研究小组在几年前的研究中已发明，在幼鼠大脑皮层原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理卵白，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乐成能性突触，释放出兴奋性或抑制性的递质。不但还在发育的星形胶质细胞爆发转变，并且因受损而被激活的成熟大脑中的星形胶质细胞也能爆发这种转变。这一发明使研究职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要领。（泉源：新华社 班玮）
【点评】
通过基因手艺直接刷新和转变组织细胞类型的例子。关于体外再生神经细胞的研究有参考价值，但现在看不出有任何治疗上的适用价值。
【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.