干細(xì)胞治皮膚病.doc

LATEST NEWS A graft of human skin genetically corrected to make collagen VII protein green 綠色標(biāo)記的為人皮膚中的膠原蛋白層 Stem cells show potential for treating rare skin disease 干細(xì)胞在治療罕見(jiàn)皮膚病方面展現(xiàn)巨大 潛力 By Jocelyn Kaiser 26 November 2014 2 00 pm 6 Comments 科學(xué)家們?cè)诶酶杉?xì)胞治療罕見(jiàn)皮膚病方面跨出了重要的一步 這種皮 膚病是大炮型表皮松懈病 只是輕微的碰觸就會(huì)使患者皮膚產(chǎn)生水泡 最近發(fā) 表的一篇報(bào)道通過(guò)三個(gè)實(shí)驗(yàn)室的通力合作以及一系列動(dòng)物實(shí)驗(yàn)為治療這種皮膚 疾病提供了科學(xué)依據(jù) 大皰型皮膚松懈病發(fā)病率低 在兩萬(wàn)新生兒中有一名患病 全球約有 50 萬(wàn)人患有此病 這種疾病屬于基因缺陷病 是由于編碼連接上下層皮膚的膠原 蛋白的基因缺失造成 這種基因的缺失使皮膚容易破碎 產(chǎn)生水泡和褥瘡 目 前沒(méi)有治療方法 內(nèi)科醫(yī)生治療這種疾病的方法只是清理傷口和治療感染 患 有此病的兒童很容易誘發(fā)導(dǎo)致皮膚癌癥 于 45 歲左右失去生命 幾年前 科學(xué)家們利用基因治療的方法對(duì)一名大皰性表皮松懈病患者進(jìn) 行了治療 科學(xué)家們?nèi)』颊叩钠つw細(xì)胞在體外培養(yǎng) 經(jīng)病毒轉(zhuǎn)染修復(fù)缺陷基因 繼續(xù)培養(yǎng)基因完整的皮膚細(xì)胞成為完整的皮膚 之后將次皮膚移植到病人的大 腿上 盡管經(jīng)修飾的皮膚生存了下來(lái) 但是使用病毒存在的潛在風(fēng)險(xiǎn)和培養(yǎng)全 身大面積皮膚的難度使科學(xué)家不得不尋求另外的治療方法 幾個(gè)研究團(tuán)體將目光投向了多能干細(xì)胞治療 多能干細(xì)胞是通過(guò)重編碼 誘導(dǎo)體細(xì)胞去分化成為胚胎樣干細(xì)胞的 多能干細(xì)胞可以被誘導(dǎo)成為各種與個(gè) 人基因匹配的成體組織 從而減少了被免疫系統(tǒng)排異的可能性 哥倫比亞大學(xué)研究團(tuán)隊(duì)在誘導(dǎo)多能性干細(xì)胞過(guò)程中發(fā)現(xiàn) 來(lái)自大皰性皮 膚松懈病患者皮膚細(xì)胞在誘導(dǎo)過(guò)程中造成疾病的突變基因消失 變成為健康細(xì) 胞 科學(xué)家們將這些基因能夠恢復(fù)的細(xì)胞誘導(dǎo)為多能干細(xì)胞 然后將這些干細(xì) 胞誘導(dǎo)為角化細(xì)胞 這些細(xì)胞中表達(dá)病變皮膚細(xì)胞中的缺失的膠原蛋白 將這 些角化細(xì)胞移植到小鼠后背未發(fā)生免疫排異 之后在小鼠后背上長(zhǎng)成人皮膚 并且能夠合成新的膠原蛋白 利用這樣的方法治療這種皮膚病能夠避免基因治 療的可能的危險(xiǎn) 而且這種療法更加簡(jiǎn)單明了 但是 只有 20 30 的大皰性皮膚病患者能夠產(chǎn)生恢復(fù)性皮膚細(xì)胞 因此 另外一些研究團(tuán)隊(duì)采取了另外一種更加傳統(tǒng)的治療方法 在斯坦福大學(xué) 的科學(xué)家進(jìn)行了一項(xiàng)新的研究 他們?nèi)〈蟀捫云つw患者的皮膚細(xì)胞誘導(dǎo)為多能 性干細(xì)胞 之后對(duì)此干細(xì)胞的基因進(jìn)行基因修復(fù) 最后誘導(dǎo)為角化細(xì)胞 這些 措施可能會(huì)帶入有害突變 因?yàn)榛颊吒杉?xì)胞中可能攜帶癌癥突變基因 但是 斯坦福團(tuán)隊(duì)通過(guò)基因篩選和只培養(yǎng)擴(kuò)增無(wú)突變基因的多能干細(xì)胞的方法降低了 存在的風(fēng)險(xiǎn) 這些干細(xì)胞在小鼠后背上能夠生存一個(gè)月之久 前兩個(gè)研究團(tuán)隊(duì)都沒(méi)有做有關(guān)的動(dòng)物實(shí)驗(yàn) 奧地利科學(xué)院分子生物學(xué)實(shí) 驗(yàn)室的科學(xué)家們利用干細(xì)胞的方法治療了患有大皰性皮膚松懈癥的小鼠 他們 取基因缺陷鼠的皮膚細(xì)胞在體外誘導(dǎo)為多能性干細(xì)胞 之后修復(fù)了缺陷基因 然后誘導(dǎo)干細(xì)胞成為纖維母細(xì)胞 之后將這些細(xì)胞注射到患病小鼠皮下 這些 細(xì)胞在小鼠皮下形成了皮膚層 并存活了 18 個(gè)周 這三篇文章同時(shí)發(fā)表在科學(xué)轉(zhuǎn)化醫(yī)學(xué)雜志 Science Translational Medicine 上 斯坦福大學(xué)的 Anthony Oro 說(shuō)這些結(jié)果為大皰性皮膚松懈病 的治療帶來(lái)了新希望 他們團(tuán)隊(duì)和哥倫比亞團(tuán)隊(duì)同時(shí)申請(qǐng)了創(chuàng)建多能干細(xì)胞治 療大皰性皮膚松懈癥的基金 盡管這些研究為治療帶來(lái)了希望 但是這些結(jié)果也展現(xiàn)出來(lái)一些挑戰(zhàn) 紀(jì)念斯隆凱特林癌癥中心的干細(xì)胞學(xué)家 Lorenz Studer 評(píng)論道 研究者還沒(méi) 有使皮膚細(xì)胞生存時(shí)間延長(zhǎng)了培養(yǎng)方案 明尼蘇大學(xué)的科學(xué)家 Jakub Tolar 研究了這幾篇關(guān)于大皰性皮膚松懈病 的研究后提出了另一種存在的問(wèn)題 皮膚移植不能夠解決患者體內(nèi)來(lái)自腸道和 食道的問(wèn)題 并且 他提出了更加冒險(xiǎn)但是更全面的解決方法 利用多能干細(xì) 胞的方法制造出基因健全的細(xì)胞后進(jìn)行骨髓移植 同樣 他也為這三個(gè)研究團(tuán) 隊(duì)獲得如此結(jié)果感到高興 Stem cells show potential for treating rare skin disease Researchers 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 Penninger s 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 mice s 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 haven t yet found the right recipe for producing human skin cells that live longer than a few weeks This therapy is still kind of on hol