干细胞治皮肤病(9页).doc

-干细胞治皮肤病-第 9 页LATEST NEWSA graft of human skin genetically corrected to make collagen VII protein (green).绿色标记的为人皮肤中的胶原蛋白层。Stem cells show potential for treating rare skin disease干细胞在治疗罕见皮肤病方面展现巨大潜力By Jocelyn Kaiser 26 November 2014 2:00 pm 6 Comments 科学家们在利用干细胞治疗罕见皮肤病方面跨出了重要的一步，这种皮肤病是大炮型表皮松懈病，只是轻微的碰触就会使患者皮肤产生水泡。最近发表的一篇报道通过三个实验室的通力合作以及一系列动物实验为治疗这种皮肤疾病提供了科学依据。 大疱型皮肤松懈病发病率低，在两万新生儿中有一名患病，全球约有50万人患有此病。这种疾病属于基因缺陷病，是由于编码连接上下层皮肤的胶原蛋白的基因缺失造成，这种基因的缺失使皮肤容易破碎，产生水泡和褥疮。目前没有治疗方法；内科医生治疗这种疾病的方法只是清理伤口和治疗感染。患有此病的儿童很容易诱发导致皮肤癌症，于45岁左右失去生命。 几年前，科学家们利用基因治疗的方法对一名大疱性表皮松懈病患者进行了治疗，科学家们取患者的皮肤细胞在体外培养，经病毒转染修复缺陷基因，继续培养基因完整的皮肤细胞成为完整的皮肤，之后将次皮肤移植到病人的大腿上。尽管经修饰的皮肤生存了下来，但是使用病毒存在的潜在风险和培养全身大面积皮肤的难度使科学家不得不寻求另外的治疗方法。 几个研究团体将目光投向了多能干细胞治疗，多能干细胞是通过重编码诱导体细胞去分化成为胚胎样干细胞的。多能干细胞可以被诱导成为各种与个人基因匹配的成体组织，从而减少了被免疫系统排异的可能性。 哥伦比亚大学研究团队在诱导多能性干细胞过程中发现：来自大疱性皮肤松懈病患者皮肤细胞在诱导过程中造成疾病的突变基因消失，变成为健康细胞。科学家们将这些基因能够恢复的细胞诱导为多能干细胞，然后将这些干细胞诱导为角化细胞，这些细胞中表达病变皮肤细胞中的缺失的胶原蛋白。将这些角化细胞移植到小鼠后背未发生免疫排异，之后在小鼠后背上长成人皮肤，并且能够合成新的胶原蛋白。利用这样的方法治疗这种皮肤病能够避免基因治疗的可能的危险，而且这种疗法更加简单明了。 但是，只有20% - 30%的大疱性皮肤病患者能够产生恢复性皮肤细胞，因此，另外一些研究团队采取了另外一种更加传统的治疗方法。在斯坦福大学的科学家进行了一项新的研究，他们取大疱性皮肤患者的皮肤细胞诱导为多能性干细胞，之后对此干细胞的基因进行基因修复，最后诱导为角化细胞。这些措施可能会带入有害突变，因为患者干细胞中可能携带癌症突变基因。但是，斯坦福团队通过基因筛选和只培养扩增无突变基因的多能干细胞的方法降低了存在的风险。这些干细胞在小鼠后背上能够生存一个月之久。 前两个研究团队都没有做有关的动物实验，奥地利科学院分子生物学实验室的科学家们利用干细胞的方法治疗了患有大疱性皮肤松懈症的小鼠。他们取基因缺陷鼠的皮肤细胞在体外诱导为多能性干细胞，之后修复了缺陷基因，然后诱导干细胞成为纤维母细胞，之后将这些细胞注射到患病小鼠皮下，这些细胞在小鼠皮下形成了皮肤层，并存活了18个周。 这三篇文章同时发表在科学转化医学杂志(Science Translational Medicine) 上，斯坦福大学的Anthony Oro说这些结果为大疱性皮肤松懈病的治疗带来了新希望。他们团队和哥伦比亚团队同时申请了创建多能干细胞治疗大疱性皮肤松懈症的基金。 “尽管这些研究为治疗带来了希望，但是这些结果也展现出来一些挑战。” 纪念斯隆凯特林癌症中心的干细胞学家Lorenz Studer评论道，研究者还没有使皮肤细胞生存时间延长了培养方案。 明尼苏大学的科学家Jakub Tolar研究了这几篇关于大疱性皮肤松懈病的研究后提出了另一种存在的问题：皮肤移植不能够解决患者体内来自肠道和食道的问题。并且，他提出了更加冒险但是更全面的解决方法：利用多能干细胞的方法制造出基因健全的细胞后进行骨髓移植。同样，他也为这三个研究团队获得如此结果感到高兴。Stem cells show potential for treating rare skin diseaseResearchers have taken several steps toward using stem cells to treat a rare genetic disease that leaves people with skin so fragile it blisters at the slightest touch. A trio of lab and animal studies reported today could help pave the way for a clinical trial for the disorder, called epidermolysis bullosa (EB).Although EB is quite rare, occurring in one in 20,000 births, about 500,000 people around the world suffer from some form of the disease. It is caused by defects in any of several genes that code for proteins, such as collagen, that link the top and bottom layers of skin. The gene defect creates fragile skin that easily tears, resulting in painful blisters and sores. There is no cure; physicians usually treat symptoms only by dressing wounds and treating infections. Those with severe forms of EB who survive childhood are also prone to skin cancer and often die from that by their mid-40s.A few years ago, researchers tried gene therapy in a single EB patient, using a virus to add a corrective gene to skin cells cultured from that person and then grafting sheets of them onto his legs. Although the repaired cells took hold, the risks of the virus used in the trial and challenges of growing enough cells to cover a large surface area led researchers to look for other options.Several groups have now turned to induced pluripotent stem (iPS) cells, a type of cell created by reprogramming adult cells back into an embryonic state. These iPS cells can be coaxed to grow into large quantities of various adult tissues that are genetically matched to a person and therefore less likely to be rejected by the immune system than cells from a donor.A Columbia University team pursuing the iPS cell approach recently took advantage of the fact that some EB patients have skin cells that somehow lose the disease-causing mutations and turn back into healthy cells. The scientists transformed some of these “revertant” cells into iPS cells, then from them grew skin cells called keratinocytes that expressed the type of collagen missing in the patients. When grafted onto the back of a strain of mice with a weak immune system that would not reject the cells from a different species, the keratinocytes grew into human skin and produced the correct form of collagen. Using revertant cells in this manner for EB could avoid the risks of gene therapy and “be a little more straightforward,” says study leader Angela Christiano.But only about 20% to 30% of people with EB have revertant skin cells, so other groups have taken a more traditional approach. In a second study, researchers at Stanford University in Palo Alto, California, created iPS cells from skin cells taken from three EB patients lacking a collagen different from the type studied by the Columbia team. They then fixed the genetic defect in the stem cells before turning them back into keratinocytes. These steps can potentially introduce harmful mutations, and the original cells from EB patients can also carry cancer-causing mutations. But the team reduced this risk by genetically screening and banking only iPS cells free of harmful mutations. The cells grew as skin grafts on mice for up to a month before the cells died.Neither of these studies showed that cells could help treat the disease in an animal with EB. But in the third study, researchers in Josef Penningers lab at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences in Vienna did just that by deriving iPS cells from the skin cells of mice with the same defect as the EB patients studied by the Stanford group. They then repaired the collagen gene; turned the cells into fibroblasts, another type of skin cell; and injected them under the sick mices skin. These cells formed skin layers that expressed the correct form of collagen for 18 weeks.Together, the three papers, published today in Science Translational Medicine, “should provide a lot of optimism that this approach has a lot of legs,” says Anthony Oro, who co-led the Stanford study with Marius Wernig. Both his group and the Columbia team have applied for funding to launch trials of the iPS cell treatment in EB patients.Although the reports are promising, they also show the challenges of using such cells for the skin disorder, says stem cell scientist Lorenz Studer of Memorial Sloan Kettering Cancer Center in New York City. He points out that the researchers havent yet found the right recipe for producing human skin cells that live longer than a few weeks. “This therapy is still kind of on hold until the field can achieve long-term engraftment,” Studer says.Jakub Tolar of the University of Minnesota, Twin Cities, who also studies iPS and gene therapy for EB, highlights another issue. The skin graft approach wont treat internal problems that many EB patients suffer from due to the diseases effects on the lining of the gut and esophagus. Tolar is working on a riskier, but more comprehensive solution: giving EB patients bone marrow transplants of gene-corrected cells made using iPS cells. Still, hes impressed by the current trio of papers. “Its gratifying to see they have taken it this far,” Tolar says.