Sci Transl Med:诱导干细胞有望治愈罕见皮肤病
“大疱性表皮松解”(EB)由Koebner在19世纪晚期首次提出,用以描绘一种不留瘢痕的水疱性皮肤病。EB在临床上十分罕见,大约2万个新生儿中可出现1例,全世界大约有50万患者。近日,三篇发表在《科学转化医学》的论文表明,诱导干细胞技术有望治愈这一罕见皮肤病。


“大疱性表皮松解”(epidermolysis bullosa,EB)由Koebner在19世纪晚期首次提出,用以描绘一种不留瘢痕的水疱性皮肤病。随后用于描述一组以皮肤和黏膜对机械损伤易感并形成大疱为特征的多基因遗传性皮肤病,为一组典型的侵及皮肤基底膜区的疾病。

EB在临床上十分罕见,大约2万个新生儿中可出现1例,全世界大约有50万患者,该疾病主要是因为基因缺陷导致某些皮肤组织相关蛋白如胶原蛋白缺乏,这些蛋白是联系皮肤各层细胞的重要基础。这些蛋白缺乏导致皮肤松懈,非常容易被擦伤,并形成疼痛性大水疱,目前缺乏该疾病的针对性治疗方法,只能对症处理,许多患者即使侥幸存活,也容易发生皮肤癌,寿命一般很难超过40岁。多组科学家用动物模型证明采用诱导干细胞技术有希望疗愈该罕见皮肤疾病。

几年前,科学家曾经给一名该病患者使用基因治疗,当时使用一种携带相关基因的病毒体外感染来自患者的皮肤细胞,然后将细胞片移植到患者腿部。虽然这些细胞能存活,但由于病毒存在风险,细胞数量也难以满足需要,导致科学家寻求其他方法。

一些科学家现在开始使用诱导干细胞iPS作为工具,诱导干细胞能分化成为各种细胞类型,并可以大量增殖,由于细胞可从患者自身获得,也不存在使用异体细胞的免疫排斥问题。

哥伦比亚大学的一个小组根据某些EB患者的部分细胞会自我修复突变基因转变为健康细胞的现象,将这些已经恢复正常的细胞变成iPS,这些细胞分化为可表达胶原蛋白的皮肤角质细胞。当将这些细胞移植回缺乏免疫排斥效应的小鼠,这些皮肤角质细胞可以变成人类皮肤细胞并产生正常的胶原蛋白,使用这种技术可避免基因治疗使用病毒的风险,具有更大的可行性。

不过只有20-30%的EB患者存在皮肤自我修复细胞的现象,因此这不可能成为所有患者的治疗方法,来自斯坦福大学的另外一个小组则采用缺乏表达胶原蛋白能力的患者皮肤细胞,他们采集三名EB患者的皮肤细胞,首先采用基因修饰技术改造这些基因缺陷细胞,使他们具有可表达胶原蛋白的能力,然后将这些细胞诱导成iPS和并分化为皮肤角质细胞。这种技术可以修复突变基因,理论上也可以修改致癌突变基因。这些细胞在小鼠身上形成皮肤组织后存活至少达1月以上。

上述研究并不能证明这种技术能治疗EB,来自奥地利科学院的第三个小组解决了这个问题。他们采用的方案和斯坦福大学小组的类似,不同的是使这些细胞定向分化为成纤维细胞,给患有EB的小鼠皮下注射该细胞后,这些细胞可形成皮肤细胞并可连续18周表达正常的胶原蛋白。

三篇论文今天同时在《科学转化医学》发表,哥伦比亚大学和斯坦福大学都正在申请开展iPS细胞治疗EB的临床研究经费。

来自纽约斯隆凯特灵癌症中心的干细胞学家Lorenz Studer认为,虽然这些研究很不错,但是这些研究没有找到让细胞长期存活的方法,这是制约在临床上使用的很大缺陷。明尼苏达大学干细胞学家Jakub Tolar则认为,皮肤移植并不能解决患者内脏的问题,许多EB患者主要的问题是内脏的功能障碍。Tolar现在正在采用一种更复杂的技术,给EB患者进行骨髓移植经过基因修改的iPS细胞。

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