本综述已经被中国《自然》杂志收录： http://www.nature.shu.edu.cn/CN/10.3969/j.issn.0253-9608.2020.02.003 ，转载请注明出处。 摘要：大疱性表皮松解症病人通过全身换皮已经实现了根治。从不治之症到可以治疗，皮肤干细胞疗法走过了漫长的发展历程 。从不经意间发明皮肤干细胞体外培养的技术，到利用皮肤干细胞再生皮肤组织，到治疗深度烧伤病人和角膜灼伤，最后到治疗遗传性皮肤病。这个临床医学上的突破是干细胞治疗和基因治疗结合的典范。本文将回顾这一发展历程，展示科学发展的规律，为基因治疗和干细胞治疗在其它领域的发展提供思路。 关键词 基因治疗、干细胞治疗、皮肤干细胞、大疱性表皮松解症 2017 年，世界各大科技新闻网站都在关注和报道一则医学新进展：叙利亚7岁的“蝴蝶”男孩哈桑（Hassan）用自己的皮肤细胞更换了几乎全身的皮肤，因而获得了新生，再也不用承受皮肤溃烂、感染的痛苦 。这次“换皮”成功标志着曾经无法根治的绝症变为可以治疗，它是干细胞治疗发展的里程碑。科学能走到这一步，是科学家们前赴后继不断探索积累而成的。 哈桑得的是什么病？ 哈桑的皮肤就像蝴蝶的翅膀一样脆弱，他的皮肤常年起水疱、破损和感染，整个人都是血红色的；站着疼、坐着疼、躺着也疼，他常年在痛苦地生活着，挣扎在死亡的边缘。他得的是一种罕见的皮肤遗传病，临床上叫做大疱性表皮松解症（e pidermolysis bullosa ，EB ）。 皮肤是覆盖在我们人体最外层的器官，它似乎没有大脑、心脏等器官那么之光重要，但是它有两个和人生死攸关的功能：一个是作为人体与外界环境的屏障，保护人体免受外界病原体如细菌、病毒等的侵袭；另一个是皮肤还能保持体内的水分，防止人们脱水而死。此外，它还有物理防护、感觉、排汗、排油脂、调节体温等功能。 皮肤由上皮和真皮构成，上皮和真皮的交互界面是基底膜，基底膜的黏连蛋白将二者锚定在一起。细胞和细胞之间由细胞外基质构成，细胞外基质中的黏连蛋白将细胞组合在一起形成组织。如果细胞间的黏连蛋白出现功能异常，细胞间或者上皮和真皮之间出现间隙，组织间液以及免疫细胞等会充斥其间形成水疱，使皮肤受损甚至糜烂。而哈桑正是层黏连蛋白-332（laminin-332）的其中一个编码基因出现了突变。 无独有偶，新闻中也曾用“保鲜膜男孩”报道过类似的中国病人，由于皮肤常年受损，身体持续大面积处于腐烂状态并散发恶臭，父母每天在他上学前都用保鲜膜把他的身体严严实实地裹起来，以减少皮肤摩擦受伤以及掩盖恶臭。遗传性大疱性表皮松解症属于罕见性遗传病，在美国据统计大约5万个新生儿中会有一例 。迄今为止，人们发现至少有20种编码角质纤维蛋白、细胞黏连蛋白等负责细胞间锚定的基因突变导致这种疾病 。不同的基因突变决定了病人症状轻重不同，严重者皮肤或者粘膜上皮轻微摩擦、挤压都会导致水疱。除了上皮脆弱、起疱、破损和容易感染外，病人通常还伴随着其它上皮异常，如指甲和牙齿异常、严重结疤、粟立肿、角化病和色素沉着异常等 。重症患者护理不足的话通常会在婴幼儿期间死亡，而后期也容易得皮肤鳞状细胞癌而死亡。 遗传 性 大疱性表皮松解症 又可以细分为四种类型 ：1、 单纯性大疱性表皮松解症（epidermolysis bullosa simplex，EBS），这类疾病的特征是上皮内起水疱，发生变异的蛋白有角质蛋白 KRT5 、 KRT14 、负责细胞骨架连接的PLEC基因等，显性遗传居多；2、交界性大疱性表皮松解症（junctional epidermolysis bullosa，JEB），这类疾病是源于层黏连蛋白或者胶原蛋白有缺陷，导致上皮和真皮间的基底膜起水疱，通常是隐性遗传的，哈桑的laminin-332编码基因突变正是属于这一类； 3、营养不良性大疱性表 皮松解症（ dystrophic epidermolysis bullosa ，DEB)，这是另一个编码胶原蛋白 COL7A1 突变导致的 ，患者的水疱也是在基底膜中产生，可以是显性或者隐性遗传 ；4、 Kindler 综合征 （ Kindler syndrome ），它是因为负责微丝蛋白和细胞外基质相互作用 的粘着斑（focal adhesion plaques ）的基因 KIND1发生了突变，属于隐性遗传。还有一类类似的皮肤病叫做表皮松解性鱼鳞病（epidermolytic ichthyosis，EI），它早期症状与和单纯性大疱性表皮松解症类似，但是随后会产生鱼鳞藓和角化过度，这类疾病通常是因为角质蛋白KRT1或者KRT10突变引起的。 对于皮肤松解症的病人，预防措施主要是加强护理，防止皮肤受伤起疱和感染；临床干预措施主要是处理伤口、缓解疼痛、控制感染、治疗并发症等，护理成本高昂，没有根治的办法。 开端：皮肤干细胞的体外扩增 要解释哈桑的全身换皮治疗，首先要先说明皮肤干细胞在体外是如何扩增的。皮肤干细胞位于上皮的基底层，它每天复制更新替换死去和脱落的皮肤细胞。意外发明皮肤干细胞体外扩增这项技术的是来自先后在麻省理工学院和美国哈佛医学院的Howard Green教授。他最初感兴趣的是怎么从培养的小鼠畸胎瘤细胞中获取到更多的有关胚胎发育的信息，因为畸胎瘤源于生殖细胞，瘤体中会含有类似于胚胎发育形成的皮肤、毛发、牙齿、骨骼、油脂、神经组织等，所以他把畸胎瘤组织解离成单细胞后放在含有培养液中培养 。培养多天后，他实验室的研究人员生发现在成纤维细胞的背景中形成了看起来像是上皮细胞的克隆。他们实验室试图获取这种上皮细胞，但是因为分离的细胞生长很差并未成功。在体内组织中，上皮细胞和真皮细胞是紧紧地附着在一起的，他们交互的界面是基底膜；基底膜像海绵一样，吸收上皮和真皮细胞释放的因子从而相互影响和支持。因而，模拟体内的情况将上皮细胞和真皮细胞共培养有可能让上皮细胞生长得更好，畸胎瘤类似上皮的细胞也是在成纤维细胞的背景下生长形成克隆的。于是他们在培养皿中先是添加了致死剂量辐射过的3T3成纤维细胞，然后在3T3滋养细胞上再放入畸胎瘤衍生的上皮细胞，结果这些上皮细胞生长得非常好 。紧接着，他们测试人的上皮细胞，将一小片人的皮肤解离出上皮细胞，并将它们在3T3细胞支持下进行培养，也获得了成功 。 后来他们发现，上皮细胞在成纤维滋养细胞上生长，可以形成大小不等的克隆。最大的全克隆（ Holoclone ）具有最好的干性和最大的增殖能力，最小的小克隆（ Paraclone ）的干性最差且增殖能力最小，处于中间的半克隆（ Meroclone ）具有相当强的增殖潜能和干性，但小于全克隆 。这些不同干性的克隆和后面要说的组织再生和维持的能力直接相关。 皮肤干细胞再生皮肤 紧接着Howard Green教授问的问题是培养皿培养的上皮细胞是否能够再生出皮肤。他们用分散酶（dispase）将长满的人的上皮细胞整片地从培养皿上消化下来，然后将剥 离下来的细胞片移植到免疫缺陷小鼠皮肤伤口上，结果这样的细胞片在小鼠上生成了人的皮肤。由于人的皮肤形态结构与小鼠本身的皮肤不同，并且人的皮肤会特异表达一些蛋白，切片染色的结果确证在小鼠的表面长出的是人的皮肤而而非小鼠自身修复产生的皮肤 。这一结果证明，体外培养扩增的上皮细胞，具有再生皮肤的能力。这个动物实验为这一技术的临床应用奠定了坚实的基础。 皮肤干细胞治疗烧伤病人 因为体外培养的皮肤干细胞能够大量扩增，且扩增的细胞能再生皮肤，Howard Green就大胆提出假设，能否将一个已经被大面积烧伤的人的残留皮肤进行细胞培养和扩增，并将之用于大面积皮肤的再生 ？Howard Green与 Nicholas O’Connor 医生合作， 在皮肤烧伤的成年人进行小规模试验。他们用患者的小片皮肤培养的细胞片覆盖胳膊烧伤处，结果如预期一样，患者在烧伤处再生出了皮肤补丁 。这个结果证明了这一假设的可行性。 1983 年的一天，波士顿的烧伤研究所所长John Remensnyders医生打电话给Howard Green，说有一对5岁和7岁的兄弟，火焰烧伤了他们身体表面超过90%的皮肤，根本无法用常规治疗方法进行自体皮肤的移植，问他是否想要尝试他们实验室的技术，用体外大规模培养的皮肤细胞来进行移植治疗。Howard Green尽管觉得实验室从未培养过如此大量的皮肤细胞，但是鉴于两兄弟如果用常规治疗根本没有生存的机会，答应合作。他分别从两兄弟未烧伤的皮肤中取一小片皮肤，解离并培养皮肤细胞，制作成细胞片分次敷在清创后的伤口处。结果是实验成功，细胞片再生处皮肤并连接起来覆盖在表面。尽管没有再生出汗腺和毛囊，覆盖的皮肤也干燥脆弱，但是它使机体具备了防护和保水最重要的功能，两兄弟都幸存下来，并且生活了20多年 。 需要特别指出的是，因为移植的是自体的细胞，所以人体很好地接纳了新的皮肤，不会产生免疫排斥反应。这是自体干细胞移植非常重要的优势。在此之前人们也怀疑单纯上皮细胞覆盖根本解决不了烧伤的问题，因为真皮无法再生的话，皮肤缺乏韧性。但是后面的实验结果证明，在上皮细胞覆盖伤口后，真皮也在它下面再生出来了 。 角膜干细胞治疗 由于角膜上皮细胞与皮肤上皮细胞都来自于胚胎期人体最外层的一层细胞，所以角膜上皮细胞与皮肤上皮细胞有很多相似的性质。角膜干细胞位于角膜缘 ，有人尝试用Howard Green开发的办法，用3T3成纤维滋养细胞培养角膜缘细胞，取得了成功 。有一类病人，因为一只眼睛被化学灼伤破坏了角膜缘干细胞而失明。意大利M.Deluca和G.Pellrini实验室采集正常眼睛的角膜缘干细胞（健康眼睛被采集角膜缘干细胞后，余下的干细胞会再生补充而不受什么影响），并用滋养细胞对角膜缘干细胞进行培养后，之后更是采用最新改进的方法，将角膜缘细胞放在纤维蛋白基质中来培养，这样细胞很容易成片剥离。剥离的细胞片敷在去除不透明组织的失明的眼睛上，结果再生出了完整的角膜 。值得一提的是，干细胞移植修复是永久性的修复，因为干细胞在组织中定植后可以源源不断地供给以维持细胞的代谢更新。在超过100例的病人中有80%的症状得到了缓解，有的病人在移植后超过10年，一直拥有完好的角膜上皮，眼睛也永久复明 。 干细胞与基因改造结合治疗遗传性皮肤病 M.Deluca 和G.Pellrini实验室还尝试将表皮细胞导入基因来治疗遗传性皮肤病。他们研究的交界型大疱性表皮松懈症患者，在等位基因Laminin 5- ß3 中的一个发生缺失，另一个等位基因包含了一个移码突变。他们用逆转病毒载体将Lam5-ß3的全长cDNA导入到病人体外培养的皮肤细胞，然后移除胳膊部分破损的皮肤并用体外培养的且经过基因改造的细胞片取代，结果在治疗部位的皮肤获得了很好的修复 。虽然他们仅是取代了一小部分皮肤， 但是这个试验成功后，全身换皮治疗大疱性松解症在理论上已经完全可行了。 几年之后就发生了开头的一幕，同样是M.Deluca实验室取一小片哈桑的皮肤，将它解离出来的皮肤细胞进行体外培养，并用逆转录病毒导入缺失的基因；皮肤细胞大量扩增源源不断获得细胞片，用细胞片分次移植和取代病变的皮肤。几个月后，哈桑80%的皮肤获得了更换，他再也不用忍受皮肤损伤带来的痛苦，从此他也可以像其他孩子一样在阳光下跑跳玩耍了 。 展望 哈桑的例子是医学发展的典型的例子，从不治之症到最后可以治疗，一切都源于基础研究的进展。Howard Green在他回忆的文章里面也不无感慨地说：“在1974年，我还没打算要研究体外细胞疗法或者治疗人类烧伤。在那时，当时的想法是：可以从培养的小鼠畸胎瘤中获取到更多的有关胚胎发育的信息。”正是对于科学问题的追问，才诞生了皮肤干细胞体外培养的方法，也才在后面一步步地演进，发展出可以治疗大面积烧伤、眼睛灼伤以及遗传性皮肤病的新疗法。 当然，这种方法治疗大面积皮肤烧伤以及大疱性表皮松解症目前并没有完全推广开来，其中最主要的障碍就是高昂的治疗成本。细胞在体外大量培养扩增、分多次反复手术替换皮肤、病人在此过程中的防护都需要大量的人力物力。 人们已经发现，培养的上皮细胞的干性维持对于上皮再生至关重要。角膜上皮移植中失败的例子，多数是因为在角膜缘干细胞的分离和体外培养扩增的过程中出现了分化，因而再生角膜难以为继。而在哈桑的例子中，人们发现再生皮肤中少量的皮肤干细胞渐渐地取代了其它移植的干性不强的细胞 。如何调试培养条件，在体外培养中最大限度地模拟体内的环境，保持细胞的干性是未来最重要的课题。 此外，逆转录病毒随机插入的办法可能会导致某些细胞发生癌变，大的基因片段在逆转率病毒中进行高效的克隆和包装都有一定难度，而且一些显性遗传的突变无法用导入基因的方式修复。人们现在正在尝试用基因编辑新技术，比如TALENs 和 CRISPR/Cas9的办法在体外对体外培养的细胞进行基因修复，在实验室中取得了很好的效果 。 Hirsch T, Rothoeft T, Teig N, Bauer JW, Pellegrini G, De Rosa L et al. 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生物3D打印课题组(EFL团队)2019年度回顾 忙碌的日子总是过的很快，2019年EFL（Engineering for Life）团队是一个内强素质，外塑形象的关键节点。这几年围绕生物3D打印，我们在打印工艺、打印装备、生物墨水耗材等经历了多次迭代，对生物3D打印的理解也越来越深，今年围绕体外疾病模型的高效构建、类器官的打印、大尺寸组织的体外重建等层面取得了显著进步。在基础研究层面，今年我们在高水平期刊上发表了系列文章，阐述我们对生物3D打印的理解，有幸其中的两篇被选为了封面文章。在成果转化方面，EFL团队的产业化公司已初见规模，后续发展思路也逐步清晰。团队所提供的生物3D打印解决方案已在为国内外近300个课题组的高水平科研提供支持。 回首2019年，最想说的一个词就是感恩，感谢浙江大学及机械工程学院提供了包容而自由的工作环境，感谢各位师长、同事，感谢众多的朋友，感谢木渎镇、吴中区、苏州市，感谢吴中科创园及苏州智能制造研究院，没有各级领导及朋友一直以来的关心与支持，我们走不到今天。EFL团队在你们的关注下成长，我们也一定会秉承浙大的求是作风，脚踏实地，一步一个台阶的走好。 感谢团队各位同学的辛苦工作，感谢产业化公司的各位同事，EFL所取得的点滴进步都是你们拼命干出来的，你们用实际行动诠释了不忘初心，为你们点赞！ 一、基础研究 1. Materials Horizons （IF=14.356） 封面，全水凝胶器官芯片制造新方法 一句话概括 ：在水凝胶上首次构建了完整的血供循环系统（动脉-毛细血管-静脉），证明毛细血管也是可以体外构建的。 论文信息 ： Nie J, Gao Q, Xie C, et al. Construction of multi-scale vascular chips and modelling of the interaction between tumours and blood vessels . Materials Horizons, 2020. 2. Advanced Healthcare Materials （IF=6.27）封面，载细胞微丝/纤维状类器官，何时成为临床产品？ 一句话概括 ：证明了载细胞水凝胶微丝能发育为功能化组织、能快速批量稳定制造、还能像细胞一样被冻存，很有希望成为微组织银行中的批量存储单元，具备后续临床化潜力。 论文信息： Shao L, Gao Q, Xie C, et al. Bioprinting of Cell‐\Laden Microfiber: Can It Become a Standard Product? . Advanced healthcare materials, 2019, 8(9): 1900014. 3. Biofabrication （IF=7.236），高生物活性水凝胶GelMA复杂支架打印 一句话概括：以GelMA生物水凝胶为生物墨水，定义了生物材料可打印性研究规范，解决了GelMA水凝胶复杂结构的高效打印。 论文信息： Gao Q, Niu X, Shao L, et al. 3D printing of complex GelMA-based scaffolds with nanoclay . Biofabrication, 2019, 11(3): 035006 . 4. ACS Applied Materials Interfaces (IF=8.1) 通用的3D 打印多材料高弹性硅胶方法 一句话概括 ：给出了硅胶及PDMS类软材料一种通用3D打印解决方案，可实现各种硅胶的高效、高质打印而不改变原有的力学性能，建立了打印的理论模型，系统地分析了硅胶类高弹性体的可打印性，首次实现了2000%高弹硅胶的打印。 论文信息 ： Zhou L, Gao Q, Fu J, et al. Multi-Material 3D Printing of Highly Stretchable Silicone Elastomer . ACS applied materials interfaces, 2019. 5. Materials Design （IF=5.77），3D打印超高精度生物支架调控细胞生长 一句话概括 ：可打印从20微米到3微米线宽的生物支架，实现在同一个支架上不同区域有不同的力学性能，揭示细胞还可以像植物攀爬架子式的生长。 论文信息 ： Xie C, Gao Q, Wang P, et al. Structure-induced cell growth by 3D printing of heterogeneous scaffolds with ultrafine fibers . Materials Design, 2019, 181: 108092. 6. Materials Science and Engineering: C （IF=4.959），多尺度3D打印高生物相容性及力学强度兼具的组织工程支架 一句话概括 ：打印多级支架结构，超细支架（3微米丝径）提升支架的生物兼容性、常规尺寸支架（100微米丝径）提供足够的强度。 论文信息 ： Gao Q, Xie C, Wang P, et al. 3D printed multi-scale scaffolds with ultrafine fibers for providing excellent biocompatibility . Materials Science and Engineering: C, 2020, 107: 110269. 7. Advanced Functional Materials （IF=15.621），液态金属-硅胶墨水实现柔性电子的全打印制造 一句话概括 ：提出了一种独特的液态金属-硅胶墨水和相应的多材料3D打印工艺用以制造全打印的液态金属基柔性电子设备。 论文信息 ： Zhou L, Fu J, Gao Q, et al. All ‐\ Printed Flexible and Stretchable Electronics with Pressing or Freezing Activatable Liquid ‐\ Metal – Silicone Inks . Advanced Functional Materials, 2019. 8. Biofabrication （IF=7.236）， 柔性线框模具实现微纳结构的无损伤脱模/高精度3D打印助力水凝胶类生物材料微纳结构精准制造 一句话概括 ：针对生物脆性材料如生物水凝胶，发展了全新的无损脱模思路，可实现微纳结构的低成本、高质量制造，适用于非硅材料的微加工。 论文信息 ： Lv S, Nie J, Gao Q, et al. Micro /nanofabrication of brittle hydrogels using 3D printed soft ultrafine fiber molds for damage-free demolding . Biofabrication, 2019. 9. Biomaterials Science （IF=5.251）， 生物3D打印带纤维GelMA微球：三维共培养新思路 一句话概括 ：微球中集成微丝，大幅提升生物3D打印多细胞类器官结构的能力。 论文信息 ： Xie M, Gao Q, Qiu J, et al. 3D biofabrication of microfiber-laden minispheroids: a facile 3D cell co-culturing system . Biomaterials science, 2020. 10. Asian Journal of Pharmaceutical Sciences （IF=4.016），邀请综述， 生物3D打印进展综述：从打印方法到生物医学应用 一句话概括 ：我们认为后续广泛应用的三个生物3D打印技术是投影式光固化打印、悬浮支撑打印及同轴打印，生物墨水的要点是在可打印性、生物相容性和机械性能三者中找到平衡。 论文信息 ： Gu Z, Fu J, Lin H, et al. Development of 3D Bioprinting: From Printing Methods to Biomedical Applications . Asian Journal of Pharmaceutical Sciences, 2019. 11. Advanced Healthcare Materials （IF=6.27），带营养输送网络同步生物3D打印方法 一句话概括 ：提出共轴生物3D打印，解决直接打印大尺寸多孔载细胞支架易坍塌问题。 论文信息 ： Shao L, Gao Q, Xie C, et al. Synchronous 3D Bioprinting of Large ‐\ Scale Cell ‐\ Laden Constructs with Nutrient Networks . Advanced Healthcare Materials, 2019. 二、生物3D打印科普 12. 在Bio-Design and Manufacturing开始专栏，系统介绍生物3D打印的各个内容 一句话概括 ：推进生物3D打印的普及，我辈责无旁贷，以科普拉近生物3D打印与普通研究人员的距离。 敬请关注 Bio-Design and Manufacturing 杂志Why choose 3D bioprinting?系列文章，创刊不到两年的SCI检索杂志BDM欢迎再生医学领域的优质稿源。 Why choose 3D bioprinting? Part I: a brief introduction of 3D bioprinting for the beginners .Bio-Design and Manufacturing ， 2019 13. 应邀撰写了一篇GelMA水凝胶生物3D打印的Protocol，带视频，系统介绍微球、微丝、复杂支架等的制造工艺 GelMA 生物 3D 打印的 视频教程论文： Xie, M., Yu, K., Sun, Y., Shao, L., Nie, J., Gao, Q., Qiu, J., Fu, J., Chen, Z., He, Y. Protocols of 3D Bioprinting of Gelatin Methacryloyl Hydrogel Based Bioinks. J. Vis. Exp. (154), e60545, doi:10.3791/60545 (2019). 视频地址： https://www.bilibili.com/video/av80697900/ 14. 录制了一门3D打印的MOOC课程，对3D打印感兴趣的朋友可选不同主题看看。 题目：“3D打印：从原理到创新应用”，在大学MOOC及智慧树平台上都有 三、生物3D打印产业转化 15. 产业化三款针对不同场景的生物3D打印机，得到了众多朋友的认可；EFL-GM系列光固化GelMA水凝胶家族也日益壮大，可模拟不同软组织硬度、不同软组织成分；还有光固化透明质酸、葡聚糖、自带荧光的水凝胶等衍生产品。 EFL(Engineering for Life) 公众号，欢迎关注
https://www.nature.com/naturecareers/job/recruitment-of-faculty-for-guangzhou-regenerative-medicine-and-health-guangdong-laboratory-guangzhou-regenerative-medicine-and-health-guangdong-laboratory-grmhgdl-711635utm_medium=naturecareersutm_campaign=711635?from=timeline Recruitment of Faculty for Guangzhou Regenerative Medicine and Health Guangdong Laboratory Guangzhou Regenerative Medicine and Health Guangdong Laboratory Guangzhou, China Introduction Guangzhou Regenerative Medicine and Health Guangdong Laboratory, or GRMH - GDL , was founded as one of the first provincial laboratories on 22 December 2017. The laboratory are dedicates to 4 directions: frontier theoretical and technological research on stem cells and regenerative medicine, research on remodeling of tissues and organs, precision medicine preclinical study, and research on the application of regenerative medicine. The laboratory is aiming to develop the reserves for constructing National Laboratories in Guangdong Province and operated as a public institution. GRMH - GDL offer 1. Internationally competitive remuneration and generous start-up package. 2.Exceptional research platform and a variety of development opportunities for Principal Investigator and Associate Professor : General Pain Institute About our center : General Pain Institute ( GPI ) is one of the scientific research centers in GRMH - GDL and headed by Dr. Horace H. Loh, who is an Academician of the Academia Sinica in Taiwan, China, Regents Professor and former Head of the Department of Pharmacology, University of Minnesota. Research Directions: GPI focuses on pain-related research which including: 1) to discover new targets for treating pain and develop new, effective and safe analgesic agents by revealing the physiological and psychological mechanisms of pain; 2) to study the side effects of addiction and abuse of the current analgesic agents, and to reduce the addiction and drug dependence while retaining the original analgesic effects; 3) to investigate the mechanisms of pathogenesis and develop drugs for other neurological diseases; 4) try to combine the traditional drug treatment with regenerative medicine to explore the new therapy methods for neurological diseases. Position and Qualifications: Principal Investigator and Associate Professor: 1. Must have a Ph.D.in cell biology, neurobiology, pharmacology, molecular biology, bioinformatics with strong research experiences and accomplishments. 2. PI should no more than 45 years old and AP should no more than 40 years old. (If the applicants show great excellence, the age limitation can be flexible.) Applications need to include: Please submit a full CV, two-page summary of research interest in the future, two letters of recommendation and other documents that can prove academic qualifications to the email: zheng_hui@gibh.ac.cn and/or miao_xiaoli@grml-gdl.cn Center of Chemistry and Chemical Biology About our center : Center of Chemistry and Chemical Biology ( CCCB ) is dedicated to solving key problems in chemistry and chemical biology with frontier technologies. Our center will establish and develop the most cutting-edge technologies, including automatic synthesis, high-throughput screening, AI-assisted drug design, machine learning for reaction prediction and synthetic route design. With the aims to set the trends of advanced research and the direction of interdisciplinary development, CCCB is committed to build an open platform for knowledge exchange, science innovation, project collaboration and talents training. CCCB is seeking highly motivated and experienced scientists with proven track record in the fields of organic synthesis, medicinal chemistry, chemical biology, computational chemistry and machine learning to fill up the Principal investigators, Associate Professor positions. Research Directions: 1. Organic chemistry methodology development 2. Automatic synthesis 3. High-throughput screening and parallel synthesis 4. Medicinal chemistry research for development of chemical probes and new medicines 5. AI-assisted drug design, machine learning for reaction prediction and synthetic route design 6. Development of technical platforms for new therapeutic modalities, DNA encoded library, proteolysis targeting chimera ( PROTAC ) 7. Development of novel drug delivery systems. Qualifications: 1.PhD in organic chemistry, medicinal chemistry, chemical biology, bioinformatics, computational chemistry or other related fields. 2.Experience in above disciplines with proven track record of publications in scientific journals. 3.Proven ability to solve critical business and scientific problems. 4.Good communication skill 5.Full professional proficiency in English. Applications need to include: A cover letter, curriculum vitae, three reference letters and future research plan should be sent to liao_kuangbiao@grmh-gdl.cn with subject of “Position and Name” . The Advanced Institute for Regenerative Medicine About our center: The Advanced Institute for Regenerative Medicine ( AIRM ) is a joint research institute of the GRMH - GDL and The Chinese University of Hong Kong. The Advanced Institute focuses on basic research in stem cells and regenerative medicine, aiming to build a world-class scientific research center, and strives to become an important part of the world-class science and technology innovation center in Guangdong, Hong Kong and Macau. Research Topics: 1. Orthopaedic research as a study of the biological activities underlying the development, growth, function, and health of skeletal tissues. 2. Functional genomics and epigenetic regulation of development in health and diseases. 3. Musculoskeletal disorders, including osteoporosis, osteonecrosis and osteoarthritis. 4. Translational application of mesenchymal stem cells for musculoskeletal disease therapy. 5. Molecular control of pluripotent stem cells; Gene therapy and cell therapy. 6. Micro/nano biofabrication based on 3D bioprinting and microfluidic techniques for regenerative medicine applications, including organ regeneration, regulation of stem cell fate and differentiation. Position and Requirements: Associate Professors (12 openings) should have: 1. a PhD, MD, or DVM degree or its equivalent in biological and biomedical sciences or related disciplines; 2. solid postdoctoral research experience in equivalent field(s) for at least two years, and oversea study/research experience is preferred; 3. a competitive track record of research and publication in top peer-reviewed scientific journals in one or more related areas; 4. expertise in using cutting-edge technologies in biochemistry, molecular biology, cell imaging, bioinformatics, genomics, molecular genetics, stem cells, transgenic animal and imaging, animal models of human diseases, biomaterials, 3D bioprinting, and/or microfluidics in their studies; Applications need to include: 1. A detailed CV that includes basic personal information, educational and professional background, research experience, mobility experience, major academic achievements/awards, list of publications/patents, and copies of relevant certificates). 2. Personal statement that highlights the candidate’s research experience and interests. 3. At least three academic or professional reference letters. All applications should be sent to: Dr KONG Ling, kong_ling@grmh-gdl.cn ; Dr WANG Yaofeng, wang_yaofeng@grmh-gdl.cn . Center of Cell Lineage and Atlas About Our Center: Center of cell lineage and atlas ( CCLA ) is one of the founding research center at Regenerative Medicine and Health Guangdong Laboratory ( GRMH - GDL ), aiming to deciphering the principles underlying cell fate transition and intercellular interaction, probing the regulatory nature of cell lineages in development and disease. CCLA is seeking outstanding individuals for positions of full-time Professor and Associate Professor in diverse disciplines of stem cell biology and translational medicine. Research Directions: 1. Technology development and application of single-cell omics. 2. Super-resolution imaging or in toto imaging. 3. Cell migration and self-organization on development. 4. Genetic and single-cell lineage tracing for tissue organization . 5. Epigenetic regulation in cell fate determination. 6. Embryonic development and in vitro organogenesis. Qualifications: 1. PhD in cell biology/molecular biology/developmental biology/genetics/bioinformatics or related field, with academic or industrial experience on stem cell biology, single-cell study and/or tissue lineages is preferred. 2. A proven track record of publications in high quality scientific journals. 3. Ability to work both independently and collaboratively, to lead multidisciplinary teams, with strong sense of responsibility Applications need to include: Please submit a full CV, two-page summary of research proposal, and other documents that can prove academic qualifications to the email: ccla@grmh-gdl.cn . The Center for Systems Biology About Our Center: The Center for Systems Biology in Development and Cancer ( SBDC ), as part of GRMH - GDL , addresses tissue anlage formation, cell fate determination, and differentiation. In-depth molecular approaches intend to explore mechanisms that promote invertebrate to vertebrate adult morphogenesis and organogenesis using high-resolution mapping of cell lineage and cell assembly leading to functional organs. State-of-the-art technologies will implement scaffolds and optimised culture conditions for tissue engineering and organ regeneration. SBDC also addresses inflammation and cancer. Among other themes, cancer stem cells/tumor initiating cells, and tumor heterogeneity will be explored through genetic, epigenetic and metabolic approaches. Refractoriness to treatments, that drives recurrence will be unravelled to identify the “Achilles’ heel” of tumors. SBDC is seeking outstanding individuals for positions of Research Professor and Associate Professor in the above areas. Applications need to include: Candidates should submit a curriculum vitae, a statement of expertise and research interest, pdfs of the three most significant publications and three reference letters to: bchtjp@nus.edu.sg We also have Postdoctoral Fellows/Research Associates available at the following centers : -————Reprogramming and Regeneration Laboratory Pia Cosma’s laboratory ( http://piacosmalab.com/ ) at GRMH - GDL ( http://en.grmh-gdl.cn ) investigates the mechanisms controlling somatic cells reprogramming and tissue regeneration. Using super resolution microscopy, the group has identified how chromatin fiber assemble in somatic and stem cells (Ricci et al., Cell 2015; Otterstorm et al., NAR 2019). Ongoing research is to study how chromatin fibers of somatic cells chage to overcome epigenetic barriers to gain pluripotency. Postdoctoral positions 1.In stem cell biology and tissue regeneration Requirements : Phd in Biology, Biomedicine, or related disciplines. Project : To set up efficient cell therapy approaches to regenerate the retina in large animals. Technical skills needed : Experience in stem cell biology and/or animal and tissue biology. Desirable: genome editing and genomics. 2. In computational analysis of super resolution imaging data Requirements : Phd in Biophysics, Mathematics or related disciplines. Dry and/or wet experience. Projects : 1.-To develop new methods for analyzing super resolution imaging data to study mechanisms of in culture and in vivo reprogramming. 2.- To apply machine learning to analyze super resolution imaging data to identify novel nuclear structures. Technical skills needed : Matlab, Python, R programming languages. Desirable: imaging analysis, machine learning, spatial modelling and statistics. Application CV,motivation letter and 2-3 reference contacts sent to pia_cosma@grmh-gdl.cn
再生医学是生命科学研究的活跃领域，是指利用生物学及工程学技术培育组织和器官并使其具备正常结构和功能的新兴领域。近年来，随着相关细胞生物学、材料科学、工程学等相关学科的进展，再生医学也越来越受到科学家及临床医生的关注。组织再生是我们关注的热点问题，也是版主的主要研究方向，会不定期的和大家分享一些新信息。 前面我们已经简单介绍过组织工程学与再生医学的概念，也聆听过美国Wake Forest Institute for Regenerative Medicinede的Dr. Anthony Atala的TED讲座。今天要奉献给大家的是麻省总院（MGH）的Dr. Harald Ott在第28届GTSC年会上的报告，题为《From Tissue Regeneration to Bioartificial Organs》。 Dr. Harald Ott及其团队致力于应用组织工程技术开发人工器官，先后在组织工程心脏、肾脏、肺脏以及肢体等复合组织的研究上取得引人注目的进展。2015年，再次以脱细胞大鼠前臂为支架通过接种肌细胞、血管内皮细胞在体外成功构建了具有活性的大鼠肢体，今日再次成为美国媒体报道的生物医学新进展之一。 如果您对组织再生、整形与修复重建外科感兴趣， 就请 扫描下面的二维码或直接查找“ 整形与修复重建外科 ”添加微信，也可 点击链接 来观看 Dr. Ott的报告，虽然比较长（13分钟），但却真的值得去听…… 请扫描下面的二维码关注 “ 整形与修复重建外科 ” 微信公众号以获得更多关于组织再生、 整形与修复重建外科的资讯。
再生医学的发展为体外培育人体组织、器官掀开了令人振奋的篇章。而组织再生也是我们感兴趣并持续努力的领域。今天，给大家推荐来自美国北卡罗来纳州Wake Forest Institute for Regenerative Medicine的Anthony Atala在TED的讲座。这个题为《Can we grow organs instead of transplanting them》的讲座条理清晰、语言简练、尤其是还有中文字幕！热爱再生医学的小伙伴有福了…… Anthony Atalas教授是Wake Forest University再生医学研究所主任、泌尿外科主任，同时他也是一名执业外科医师和再生医学领域的研究者，多年来一直关注体外培育人工组织、器官，在该领域做出了引人注目的成绩。 正如Dr. Atala所说：“Medicine is doing the better job of keeping us life.” 平均寿命的延长，人类就必将面临老龄化带来的挑战。在此背景之下，再生医学的意义就越发凸显出来了。 在TED这样的大众讲台上，Dr. Atala用简单的语言深入浅出的介绍了应用组织工程技术体外培育人工肌肉、血管、膀胱、心脏瓣膜、外耳、甚至心脏和包括3D打印技术、脱细胞组织材料的应用以及成体细胞、干细胞在人工器官培育中的应用等再生医学领域的复杂科学问题，分享了他对该领域的思考和探索…… 下面就请 扫描下面的二维码或直接查找“ 整形与修复重建外科 ”添加微信，也可 点击链接 来观看视频片段， 聆听Dr. Anthony Atala的精彩演讲吧。 如欲获得更多关于组织再生、整形与修复重建外科领域的信息，请扫描下面二维码添加“ 整形与修复重建外科”微信公众号！
Science China Life Sciences 2014年第6 期最新出版了“ Stem cells and regenerative medicine ”专题。 该期干细胞与再生医学专题共遴选5篇综述文章，总结了干细胞基础生物学和转化应用领域的成果，包括端粒和经典信号通路对干细胞和肿瘤细胞的调控，以及以此为靶点的药物发现，此外，专题分别讨论了干细胞在血液和关节炎中细胞治疗的进展。 专题篇目如下： EDITORIAL Introduction to the special topic “Stem cells and regenerative medicine” Hot! CHEN ZhiGuo, ZHANG Yu REVIEW Telomerase as a “stemness” enzyme Hot! KONG Feng, ZHENG ChengYun, XU DaWei 徐大为等探讨了端粒酶与干细胞干性及肿瘤的关系，并提出携带端粒酶突变的iPSC用于疾病模拟中的争议问题。 Paracrine signaling in stem cell renewal and in neoplastic tumor growth Hot! ZHAO Chen 赵晨等在综述中着重讲述了Hedgehog和Wnt通路的交互对话，及二者旁分泌途径对于干细胞干性维持和肿瘤发生的作用。 Targeting stem cell signaling pathways for drug discovery ： advances in the Notch and Wnt pathways Hot! An Songzhu Michael, DING Qiang, ZHANG Jie, XIE JingYi, Li LingSong 李凌松等对关键信号通路在干细胞及肿瘤中的作用进行综述，并介绍了以Notch、Wnt为靶点的药物发现进展。 From stem cells to red blood cells ： how far away from the clinical application? Hot! XIE XiaoYan, LI YanHua, PEI XueTao 裴雪涛等讨论了从造血干细胞产生红细胞的近期进展，指出体外生产红细胞的瓶颈是造血干细胞有限的体外自我更新能力，并讨论了用多能干细胞产生红细胞的策略及优化方案。 Treatment of osteoarthritis with mesenchymal stem cells Hot! WANG Wen,CAO Wei 曹卫等讨论了MSC用于骨关节炎治疗的历史、现状及临床前/临床数据，比较了不同组织来源间MSC的差异，最后探讨了干预Wnt、Hh、MAPK等通路对治疗效果的影响。 敬请关注！
Expert Opinion article predicts Nobel Prize winning paper! Read More: http://informahealthcare.com/doi/story/10.1517/news.2012.10.10.351 iPSCs的研究获得 2012 诺贝尔医学奖。 iPSCs的最初突破发表于2006。 在我们今年5月发表的综述中据显要位置，位于第7聚类中，最高被引次数，最大引用增速，。。。 纽约时报关于 2012 诺贝尔医学奖 : http://www.nytimes.com/2012/ 10/09/health/research/ cloning-and-stem-cell-discoveri es-earn-nobel-prize-in-medicin e.html?pagewanted=all 这是发表在Expert Opinion on Biological Therapy上的一篇关于再生医学领域的综述。 Chen, C., Hu, Z., Liu, S., Tseng, H. (2012) Emerging trends in regenerative medicine: A scientometric analysis in CiteSpace. Expert Opinions on Biological Therapy, 12(5), 593-608. 链接： Emerging trends in regenerative medicine: a scientometric analysis in CiteSpace 全文 本文被该刊推荐为"the pick for May 2012". Article Highlight May 2012 April 10, 2012 Helping you keep ahead of the curve! New review from EOBT uses CiteSpace software and co-citation analysis to look at new trends in regenerative medicine, our pick for May 2012 Emerging trends in regenerative medicine: a scientometric analysis in CiteSpace May 2012, Vol. 12, No. 5 , Pages 593-608 (doi:10.1517/14712598.2012.674507) http://informahealthcare.com/doi/story/10.1517/news.2012.04.10.254 图3. 聚类主题标为兰色。重要文献标为黑色。突现名词标为红色。红圈代表引文急剧增长。
http://www.gopubmed.org/web/gopubmed/2?WEB0iyduvle1bej0I2I1I00f01000j10040001rl Regenerative Medicine 7,014 documents semantically analyzed 1 2 Top Years Publications 2009 1,604 2008 1,214 2007 922 2006 793 2005 543 2004 405 2003 305 2002 186 2001 131 2010 87 2000 86 1998 84 1999 81 1996 71 1992 64 1995 63 1994 60 1997 59 1993 57 1990 45 1 2 1 2 3 4 Top Countries Publications USA 2,530 Japan 1,544 United Kingdom 531 Germany 315 Canada 208 China 198 Italy 192 Spain 127 South Korea 98 Israel 76 France 70 Switzerland 67 Australia 56 Netherlands 54 Sweden 53 Singapore 46 Portugal 41 Taiwan 41 Ireland 40 Turkey 38 1 2 3 4 1 2 3 ... 32 Top Cities Publications Tokyo 277 Pittsburgh 235 London 184 Boston 178 Winston-Salem 134 Kyoto 132 New York 124 Niigata 113 Los Angeles 108 Stanford 106 Suita 99 Philadelphia 97 Baltimore 90 Osaka 88 Bath 81 Beijing 75 Seattle 72 Yonago 71 Seoul 52 Nagoya 51 1 2 3 ... 32 1 2 3 ... 84 Top Journals Publications Regen Med 297 Stem Cells 143 Biomaterials 128 Nippon Rinsho 102 Nature 76 Stem Cells Dev 67 Tissue Eng 65 Tissue Eng Part A 64 Hepatology 59 Cell Transplant 48 Biochem Bioph Res Co 47 Blood 45 Cell Stem Cell 43 J Tissue Eng Regen Med 42 Exp Neurol 40 Proc Natl Acad Sci U S A 40 J Biomed Mater Res A 40 J Biol Chem 38 P Natl Acad Sci Usa 36 Plos One 35 1 2 3 ... 84 1 2 3 ... 773 Top Terms Publications Animals 4,060 Humans 3,898 Tissues 2,695 Regenerative Medicine 2,649 stem cell development 2,560 stem cell differentiation 2,558 Medicine 2,431 Mice 1,606 Adult 1,594 Stem Cells 1,586 Cell Differentiation 1,449 Genes 1,302 Proteins 1,209 Tissue Engineering 1,143 Patients 1,110 Therapeutics 1,093 Cells, Cultured 1,023 Rats 856 Regeneration 816 Evaluation Studies as Topic 807 1 2 3 ... 773 1 2 3 ... 1334 Top Authors Publications Nakamura T 40 Atala A 37 Nagaya N 36 Polak J 32 Endo N 29 Yoo J 28 Sacks M 28 Bhatia M 28 Matsumoto K 27 Katoh M 25 Kangawa K 25 Scadden D 24 Slack J 24 Shiota G 23 Tosh D 23 Nakanuma Y 23 Fukuda K 22 Weissman I 20 Bishop A 20 Minuk G 20 1 2 3 ... 1334 http://news.sciencenet.cn//htmlnews/2010/1/226992.shtm 报告显示中国再生医学研究跃居世界前列 英国期刊《再生医学》（ Regeneration Medicine ）1月8日刊登一份研究报告说，中国再生医学领域的研究进入21世纪以来快速发展，在国际学术期刊上发表的相关论文的数量已跃居世界第五，中国的一些研究成果夺得世界第一，其快速发展的经验值得其他发展中国家借鉴。 这份由加拿大麦克劳克林－罗特曼全球卫生中心完成的报告说，该中心检索到的中国研究人员在国际学术期刊上发表的再生医学相关论文在2000年为30多篇，但到2008年已增加到1100多篇，超过了法国、加拿大等国。 报告还指出，中国再生医学研究近年来取得了一些世界第一，比如首次成功进行人兔间核转移胚胎干细胞研究，首次利用患者大脑组织培养出的干细胞治疗该患者自身的大脑创伤等。 报告第一作者多米尼克麦克马洪对新华社记者说：中国再生医学领域发展非常迅速，毫无疑问，中国已经成为再生医疗研发竞赛中的一个领先者。 另一位报告作者哈拉索斯滕斯多蒂尔说，中国再生医学研究快速发展的原因包括国家大力支持和中国文化对胚胎干细胞研究更为宽容等。此外，中国利用各种政策吸引大批海外人才归国，打造了一支良好的紧跟国际前沿的研究队伍，这对于其他饱受人才流失问题困扰的发展中国家来说很值得借鉴。 再生医学是近年来出现的一门新兴学科，它旨在通过各种手段促进机体自我修复与再生，以治疗其所受损伤。 更多阅读 《再生医学》发表报告摘要（英文） http://www.chemspider.com/Default.aspx Summary Regenerative Medicine January 2010, Vol. 5, No. 1, Pages 35-44 , DOI 10.2217/rme.09.78 (doi:10.2217/rme.09.78) Research Article Cultivating regenerative medicine innovation in China Dominique S McMahon 1 , Halla Thorsteinsdttir 1, 2 , Peter A Singer 1 and Abdallah S Daar 1 Author for correspondence Aim: While China has become a significant contributor and prolific publisher in regenerative medicine, its role in the field is not well understood. We analyze how capacity in regenerative medicine was built in China to identify some of its main strengths and challenges. Materials methods: This case study of regenerative medicine in China is primarily based on interviews with experts in China, including researchers, policy makers, clinicians, representatives of firms and regulators. Results: Our analysis shows that diverse groups are active in this field in China. Leading research groups are contributing extensively to international peer-reviewed journals. Strong governmental support and recruitment of highly trained Chinese scientists from abroad has made it possible for China to rapidly build up capacity in regenerative medicine. However, some hospitals in China are offering stem cell therapies with limited scientific evidence supporting their efficacy/safety, and international skepticism of medical research in China presents a challenge to the development of the field. Conclusion: China has been able to catapult itself into the forefront of regenerative medicine but needs to address current regulatory challenges in order to secure its position in this emerging field. Full Text PDF (916 KB) PDF Plus (926 KB) Cited by Chris Mason , Elisa Manzotti . (2010) Stem cell nations working together for a stem cell world. Regenerative Medicine 5 :1, 1-4 Online publication date: 1-Jan-2010. Citation | Full Text | PDF (593 KB) | PDF Plus (597 KB) 全文见： Regenerative Medicine
标签: 再生医学
