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Models of Rare Diseases Based on Induced Pluripotent Stem Cells and Their Applications
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摘要: 罕见病的研究受限于样本的可获得性, 对其发病机制了解甚少阻碍了罕见病可行性治疗方法的发现。随着诱导多能干细胞(induced pluripotent stem cells, iPSCs)技术的建立和日趋成熟, 越来越多的研究开始利用iPSCs技术把患者来源的体细胞转变为iPSCs, 继而再分化为疾病相关的成体细胞。通过对发病过程和功能学分析, 患者特异性iPSCs细胞模型已成为罕见病研究的宝贵工具。iPSCs技术彻底革新了研究者对罕见病发病机制和治疗方法的研究, 尤其是iPSCs技术结合基因编辑和3D类器官方法, 使得iPSCs在各应用领域包括精准医学领域更具强大优势。本文概括介绍iPSCs技术应用于多种罕见病疾病模型建立, 以及在此基础上进行药物筛选和细胞治疗, 以期为罕见病研究者提供新的思路和启示。Abstract: Research on rare diseases is limited by the poor availability of samples. Therefore, treatment of rare diseases is hampered by insufficient understanding of the mechanisms and resultant underdevelopment of viable therapies. With the advent and development of the technology of induced pluripotent stem cells (iPSCs) in recent years, more and more studies have begun to reprogram somatic cells derived from patients into iPSCs, which then differentiate into cells affected by the disease. Through developmental and functional analysis of the differentiated cell types, these stem cell models carrying patient-specific mutations have become an invaluable tool for research on rare diseases. iPSCs technology has revolutionized the ways of exploring the mechanisms of human rare diseases and developing therapies. In particular, the combination of human iPSCs technology with recent development in gene editing and 3D organoids makes iPSC-based platforms even more powerful in each area of their applications, including precision medicine. This review overviews recent advance in human iPSC-based modeling of rare diseases. Additionally, we outline the application of iPSCs technology particularly relevant to drug screening and cell therapy, so as to provide new inspiration for researchers.
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Key words:
- rare diseases /
- induced pluripotent stem cells /
- cell diseases /
- drug screening
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表 2 采用非病毒整合方法获得诱导多能干细胞
整合方法 细胞类型 重编程因子 近似效率(%) 参考文献 仙台病毒 成纤维细胞 OSKM 1 [24] 腺病毒 成纤维细胞、肝细胞 OSKM 0.001 [25] 质粒 成纤维细胞 OSNL 0.001 [26-27] 附加体 尿细胞 OSTK+微小RNA-302-367 0.01 [28] 转座子 成纤维细胞 OSKM 0.1 [29] 蛋白 成纤维细胞 OS 0.001 [30-31] 化合物或小分子 脐静脉内皮细胞 OCT4+小分子 0.01 [32-33] 信使RNA 成纤维细胞 OSKM或OSKM+丙戊酸 1~4.4 [34] 微小RNA 脂肪间充质细胞、真皮成纤维细胞 微小RNA-200c、微小RNA-302s或微小RNA-369s 0.1 [35] K: KLF4; L: LIN28; M: c-MYC; O: OCT4; S: SOX2 
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表 3 利用诱导多能干细胞技术建立的罕见病疾病模型
罕见病名称 异常基因 诱导多能干细胞来源的功能细胞 主要成果 参考文献 肌萎缩性侧索硬化症 VCP 运动神经元、星形胶质细胞 细胞自主星形胶质细胞存活型和星形胶质细胞对共培养的运动神经元的非细胞自主效应 [43] 脊髓性肌萎缩症 SMN1 运动神经元 乙酰胆碱受体明显受损, 丙戊酸和反义寡核苷酸可改善此缺陷 [44] Charge综合症 CHD7 神经嵴细胞 体外表现出缺陷的分层、迁移、运动行为, 移植鸡胚体内表现缺陷的迁移活性 [45] 威廉姆斯综合症 Various, Chr.7 神经祖细胞 锥体神经元树突棘增加和树突变长, 卷曲蛋白9改善神经祖细胞凋亡 [46] 戈谢病 GBA1 巨噬细胞、多巴胺神经元 增加GBA活性降低α-突触核蛋白的积累, 分子伴侣恢复了葡萄糖脑苷脂酶活性、蛋白水平和降低糖脂存储 [47] 神经元细胞 溶酶体生成受损 [48] 法布瑞氏症 GLA 心肌细胞 左心室肥厚和鞘糖脂积累 [49] 庞贝氏症 GAA 骨骼肌细胞 GAA和转录因子EB共同改善骨骼肌病理状态 [50] Danon综合症 LAMP2 心肌细胞 细胞自噬异常 [51] 亨丁顿舞蹈症 HTT 神经元细胞 损害神经通路, 可能会破坏突触稳态和增加多聚谷氨酰胺重复的病理易感性 [52] 视网膜色素变性 MERTK 视网膜色素上皮细胞 视网膜色素上皮细胞吞噬功能受损; 促通读药物提高吞噬活性 [53-54] 进行性肌肉骨化症 ACVR1 骨髓间质细胞 MMP1和PAI1基因加速软骨生成 [55] 内皮细胞 骨形成蛋白可诱导内皮细胞功能障碍, 增加纤维化基质蛋白的表达, 并导致突变的下游信号通路发生变化 [56] 威尔逊氏病 ATP7B 肝细胞、神经元细胞、神经干细胞 在所有分化细胞中均检测到ATP7B突变 [57] 马凡综合症 FBN1 平滑肌细胞 非经典的p38通路调节平滑肌细胞凋亡, KLF4调控病理机制 [58] 骨髓间质细胞、平滑肌细胞 骨髓间质细胞成骨分化和微纤丝形成能力降低; 通过收缩力和钙离子流分析证明平滑肌细胞对卡巴胆碱低灵敏性 [59] 安格尔曼综合征 UBE3A 神经元细胞 神经元成熟、突触活性和可塑性受损, 非沉默父本等位基因改善表型 [60] 史-李-欧综合征 DHCR7 神经祖细胞 抑制Wnt/β-catenin信号加速神经分化 [61]
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