Balachandar Vellingiri, Dhivya Venkatesan, Gomathi Mohan, Mohanadevi Subramaniam, Venkatesh Balasubramanian, Geetha Bharathi
Human Molecular Genetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore-641 046, Tamil Nadu, India.
Stem Cell Investig. 2016 Sep 28;3:52. doi: 10.21037/sci.2016.09.05. eCollection 2016.
Human induced pluripotent stem cells (hiPSCs) are pluripotent stem cells generated from somatic cells by the introduction of a combination of pluripotency-associated genes such as OCT4, SOX2, along with either KLF4 and c-MYC or NANOG and LIN28 via retroviral or lentiviral vectors. Most importantly, hiPSCs are similar to human embryonic stem cells (hESCs) functionally as they are pluripotent and can potentially differentiate into any desired cell type when provided with the appropriate cues, but do not have the ethical issues surrounding hESCs. For these reasons, hiPSCs have huge potential in translational medicine such as disease modeling, drug screening, and cellular therapy. Indeed, patient-specific hiPSCs have been generated for a multitude of diseases, including many with a neurological basis, in which disease phenotypes have been recapitulated and proof-of-principle drug screening has been performed. As the techniques for generating hiPSCs are refined and these cells become a more widely used tool for understanding brain development, the insights they produce must be understood in the context of the greater complexity of the human genome and the human brain. Disease models using iPS from Rett syndrome (RTT) patient's fibroblasts have opened up a new avenue of drug discovery for therapeutic treatment of RTT. The analysis of X chromosome inactivation (XCI) upon differentiation of RTT-hiPSCs into neurons will be critical to conclusively demonstrate the isolation of pre-XCI RTT-hiPSCs in comparison to post-XCI RTT-hiPSCs. The current review projects on iPSC studies in RTT as well as XCI in hiPSC were it suggests for screening new potential therapeutic targets for RTT in future for the benefit of RTT patients. In conclusion, patient-specific drug screening might be feasible and would be particularly helpful in disorders where patients frequently have to try multiple drugs before finding a regimen that works.
人诱导多能干细胞（hiPSCs）是通过逆转录病毒或慢病毒载体导入多能性相关基因组合（如OCT4、SOX2，以及KLF4和c-MYC或NANOG和LIN28）从体细胞产生的多能干细胞。最重要的是，hiPSCs在功能上与人类胚胎干细胞（hESCs）相似，因为它们具有多能性，在给予适当信号时能够潜在地分化为任何所需的细胞类型，但不存在围绕hESCs的伦理问题。由于这些原因，hiPSCs在转化医学中具有巨大潜力，如疾病建模、药物筛选和细胞治疗。事实上，已经针对多种疾病（包括许多具有神经学基础的疾病）生成了患者特异性hiPSCs，在这些疾病中已经重现了疾病表型并进行了原理验证药物筛选。随着生成hiPSCs的技术不断完善，并且这些细胞成为理解大脑发育的更广泛使用的工具，必须在人类基因组和人类大脑更大复杂性的背景下理解它们所产生的见解。使用来自雷特综合征（RTT）患者成纤维细胞的iPS建立的疾病模型为RTT的治疗性药物发现开辟了一条新途径。分析RTT-hiPSCs分化为神经元时的X染色体失活（XCI）对于最终证明与XCI后RTT-hiPSCs相比，前XCI RTT-hiPSCs的分离至关重要。当前的综述项目涉及RTT中的iPSC研究以及hiPSC中的XCI，其中建议未来筛选RTT的新潜在治疗靶点，以造福RTT患者。总之，患者特异性药物筛选可能是可行的，并且在患者通常必须尝试多种药物才能找到有效治疗方案的疾病中会特别有帮助。
