2006年日本学者山中伸弥(Shinya Yamanaka)率先采用病毒载体向体细胞内导入4个转录因子(Oct4,Sox2,Klf4及c-Myc),重编程后获得类似胚胎干细胞(embryonic stem cell,ESC)和胚胎APSC多能细胞的一种类型——诱导性多能干细胞(induced pluripotent stem cell,iPSC).生成iPSC的技术相对简单和稳定,不需使用卵细胞或者胚胎,而是利用人体其他细胞,从而避免了伦理争议与法律难题.此外,生成iPSC的技术增加了干细胞在临床疾病治疗中的应用,在细胞替代性治疗、发病机制的研究、新药筛选等方面具有巨大的潜在价值.然而,随着生成iPSC的技术的发展,其弊端和问题也逐渐凸显,如原癌基因的致癌性、部分重编程的不完全性、诱导效率低下等.因此,研究者们试图寻找山中伸弥四因子的替代者并尝试优化重编程系统,如替换具有致瘤性的转录因子、添加提高重编程效率的转录因子或化合物,甚至完全摈弃转录因子而使用小分子化合物诱导重编程,从而在一定程度上避免潜在缺陷.%In 2006,the Japanese scholar Yamanaka firstly introduced the induced pluripotent stem cells (iPSC) by introducing four transcription factors (Oct4,Sox2,Klf4 and c-Myc) into the somatic cells with viral vectors.After reprogramming,the function of the iPSC is similar to embryonic stem cells (ESC) and embryonic pluripotent APSC cells.IPSC technology is simpler and more stable,using other human body cells instead of ova and embryos,thereby avoiding ethical and legal challenges.In addition,IPSC technology has further enhanced the application of stem cells in clinical disease treatments,and has great potential value in cell replacement therapies,pathogenesis researches,drug screenings and so on.However,with the development of iPSC technology,its drawbacks and problems are highlighted,such as carcinogenicity of proto oncogenes,incomplete reprogramming and low efficiency of induction.Therefore,in order to avoid these disadvantages,researchers have been trying to seek the substitutes to replace the OKSM and to optimize the reprogramming system.This review mainly focuses on the latest progress of alternative methods to the OKSM guidance system,in order to gain the iPSC with more thorough reprogramming in a safer and more efficient way,and to promote stem cell therapy for clinical application and development.
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