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基于诱导多能干细胞技术的罕见病细胞模型及其应用

时良 崔亚洲 韩金祥

时良, 崔亚洲, 韩金祥. 基于诱导多能干细胞技术的罕见病细胞模型及其应用[J]. 协和医学杂志, 2018, 9(3): 261-270. doi: 10.3969/j.issn.1674-9081.2018.03.014
引用本文: 时良, 崔亚洲, 韩金祥. 基于诱导多能干细胞技术的罕见病细胞模型及其应用[J]. 协和医学杂志, 2018, 9(3): 261-270. doi: 10.3969/j.issn.1674-9081.2018.03.014
Liang SHI, Ya-zhou CUI, Jin-xiang HAN. Models of Rare Diseases Based on Induced Pluripotent Stem Cells and Their Applications[J]. Medical Journal of Peking Union Medical College Hospital, 2018, 9(3): 261-270. doi: 10.3969/j.issn.1674-9081.2018.03.014
Citation: Liang SHI, Ya-zhou CUI, Jin-xiang HAN. Models of Rare Diseases Based on Induced Pluripotent Stem Cells and Their Applications[J]. Medical Journal of Peking Union Medical College Hospital, 2018, 9(3): 261-270. doi: 10.3969/j.issn.1674-9081.2018.03.014

基于诱导多能干细胞技术的罕见病细胞模型及其应用

doi: 10.3969/j.issn.1674-9081.2018.03.014
详细信息
    通讯作者:

    韩金祥 电话:0531-82629151, E-mail:samshjx@sina.com

  • 中图分类号: Q813.1;Q291

Models of Rare Diseases Based on Induced Pluripotent Stem Cells and Their Applications

More Information
    Corresponding author: HAN Jin-xiang Tel: 0531-82629151, E-mail: samshjx@sina.com
  • 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。
  • 图  1  诱导多能干细胞技术用于罕见病研究流程图

    表  1  产生人诱导多能干细胞的多种供体来源

    供体来源 供体细胞类型 获取过程 参考文献
    成纤维细胞 真皮成纤维细胞、牙周膜成纤维细胞 有创(皮肤活检) [5, 10]
    角质细胞 角蛋白致密上皮细胞 基本无创(发根毛囊) [11]
    脐带血 脐带血干细胞、内皮细胞 无创 [12-13]
    外周血 单核细胞、T细胞、髓系细胞 微创(静脉穿刺) [14-15]
    脂肪干细胞 脂肪前体细胞、脂肪来源的间充质干细胞 有创(抽脂) [16-17]
    神经细胞 神经干细胞 有创 [18]
    羊水 羊水细胞 有创(羊膜穿刺) [19-20]
    肝细胞 人原代肝细胞 有创 [21]
    尿细胞 肾上皮细胞、鳞状上皮细胞、移行上皮细胞、成纤维细胞 无创 [22-23]
    下载: 导出CSV

    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
    下载: 导出CSV

    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]
    下载: 导出CSV
  • [1] Cui Y, Han J. Defining rare diseases in China[J]. Intractable Rare Dis Res, 2017, 6:148-149. doi:  10.5582/irdr.2017.01009
    [2] Melnikova I. Rare diseases and orphan drugs[J]. Nat Rev Drug Discov, 2012, 11:267-268. doi:  10.1038/nrd3654
    [3] Hamlin RL, Altschuld RA. Extrapolation from mouse to man[J]. Circ Cardiovasc Imaging, 2011, 4:2-4. doi:  10.1161/CIRCIMAGING.110.961979
    [4] Onos KD, Sukoff Rizzo SJ, Howell GR, et al. Toward more predictive genetic mouse models of Alzheimer's disease[J]. Brain Res Bull, 2016, 122:1-11. doi:  10.1016/j.brainresbull.2015.12.003
    [5] Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors[J]. Cell, 2007, 131:861-872. doi:  10.1016/j.cell.2007.11.019
    [6] Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluri-potent stem cell lines derived from human somatic cells[J]. Science, 2007, 318:1917-1920. doi:  10.1126/science.1151526
    [7] Kim K, Zhao R, DoiA, et al. Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells[J]. Nat Biotechnol, 2011, 29:1117-1119. doi:  10.1038/nbt.2052
    [8] Ohi Y, Qin H, Hong C, et al. Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells[J]. Nat Cell Biol, 2011, 13:541-549. doi:  10.1038/ncb2239
    [9] Avior Y, Sagi I, Benvenisty N. Pluripotent stem cells in disease modelling and drug discovery[J]. Nat Rev Mol Cell Biol, 2016, 17:170-182. doi:  10.1038/nrm.2015.27
    [10] Wada N, Wang B, Lin NH, et al. Induced pluripotent stem cell lines derived from human gingival fibroblasts and periodontal ligament fibroblasts[J]. J Periodontal Res, 2011, 46:438-447. doi:  10.1111/j.1600-0765.2011.01358.x
    [11] Aasen T, Raya A, Barrero MJ, et al. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes[J]. Nat Biotechnol, 2008, 26:1276-1284. doi:  10.1038/nbt.1503
    [12] Giorgetti A, Montserrat N, Aasen T, et al. Generation of induced pluripotent stem cells from human cord blood using OCT4 and SOX2[J]. Cell Stem Cell, 2009, 5:353-357. doi:  10.1016/j.stem.2009.09.008
    [13] Haase A, Olmer R, Schwanke K, et al. Generation of induced pluripotent stem cells from human cord blood[J]. Cell Stem Cell, 2009, 5:434-441. doi:  10.1016/j.stem.2009.08.021
    [14] Seki T, Yuasa S, Fukuda K. Generation of induced pluripotent stem cells from a small amount of human peri-pheral blood using a combination of activated T cells and Sendai virus[J]. Nat Protoc, 2012, 7:718-728. doi:  10.1038/nprot.2012.015
    [15] Simara P, Tesarova L, Rehakova D, et al. Reprogramming of adult peripheral blood cells into human induced pluripotent stem cells as a safe and accessible source of endothelial cells[J]. Stem Cells Dev, 2018, 27:10-22. doi:  10.1089/scd.2017.0132
    [16] Aoki T, Ohnishi H, Oda Y, et al. Generation of induced pluripotent stem cells from human adipose-derived stem cells without c-MYC[J]. Tissue Eng Part A, 2010, 16:2197-2206. doi:  10.1089/ten.tea.2009.0747
    [17] Sugii S, Kida Y, Kawamura T, et al. Human and mouse adipose-derived cells support feeder-independent induction of pluripotent stem cells[J]. Proc Natl Acad Sci USA, 2010, 107:3558-3563. doi:  10.1073/pnas.0910172106
    [18] Kim JB, Greber B, Arauzo-Bravo MJ, et al. Direct reprogramming of human neural stem cells by OCT4[J]. Nature, 2009, 461:649-653. doi:  10.1038/nature08436
    [19] Cai J, Li W, Su H, et al. Generation of human induced pluripotent stem cells from umbilical cord matrix and amniotic membrane mesenchymal cells[J]. J Biol Chem, 2010, 285:11227-11234. doi:  10.1074/jbc.M109.086389
    [20] Li C, Zhou J, Shi G, et al. Pluripotency can be rapidly and efficiently induced in human amniotic fluid-derived cells[J]. Hum Mol Genet, 2009, 18:4340-4349. doi:  10.1093/hmg/ddp386
    [21] Liu H, Ye Z, Kim Y, et al. Generation of endoderm-derived human induced pluripotent stem cells from primary hepato-cytes[J]. Hepatology, 2010, 51:1810-1819. doi:  10.1002/hep.23626
    [22] Zhou T, Benda C, Dunzinger S, et al. Generation of human induced pluripotent stem cells from urine samples[J]. Nat Protoc, 2012, 7:2080-2089. doi:  10.1038/nprot.2012.115
    [23] Uhm KO, Jo EH, Go GY, et al. Generation of human induced pluripotent stem cells from urinary cells of a healthy donor using a non-integration system[J]. Stem Cell Res, 2017, 21:44-46. doi:  10.1016/j.scr.2017.03.019
    [24] Fusaki N, Ban H, Nishiyama A, et al. Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome[J]. Proc Jpn Acad Ser B Phys Biol Sci, 2009, 85:348-362. doi:  10.2183/pjab.85.348
    [25] Stadtfeld M, Nagaya M, Utikal J, et al. Induced pluripotent stem cells generated without viral integration[J]. Science, 2008, 322:945-949. doi:  10.1126/science.1162494
    [26] Si-Tayeb K, Noto FK, Sepac A, et al. Generation of human induced pluripotent stem cells by simple transient transfection of plasmid DNA encoding reprogramming factors[J]. BMC Dev Biol, 2010, 10:81. doi:  10.1186/1471-213X-10-81
    [27] Lorenzo IM, Fleischer A, Bachiller D. Generation of mouse and human induced pluripotent stem cells (iPSC) from primary somatic cells[J]. Stem Cell Rev, 2013, 9:435-450. doi:  10.1007/s12015-012-9412-5
    [28] Xue Y, Cai X, Wang L, et al. Generating a non-integrating human induced pluripotent stem cell bank from urine-derived cells[J]. PLoS One, 2013, 8:e70573. doi:  10.1371/journal.pone.0070573
    [29] Woltjen K, Michael IP, Mohseni P, et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells[J]. Nature, 2009, 458:766-770. doi:  10.1038/nature07863
    [30] Zhou H, Wu S, Joo JY, et al. Generation of induced pluripotent stem cells using recombinant proteins[J]. Cell Stem Cell, 2009, 4:381-384. doi:  10.1016/j.stem.2009.04.005
    [31] Kim D, Kim CH, Moon JI, et al. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins[J]. Cell Stem Cell, 2009, 4:472-476. doi:  10.1016/j.stem.2009.05.005
    [32] Ichida JK, Blanchard J, Lam K, et al. A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog[J]. Cell Stem Cell, 2009, 5:491-503. doi:  10.1016/j.stem.2009.09.012
    [33] Zhu S, Li W, Zhou H, et al. Reprogramming of human primary somatic cells by OCT4 and chemical compounds[J]. Cell Stem Cell, 2010, 7:651-655. doi:  10.1016/j.stem.2010.11.015
    [34] Warren L, Manos PD, Ahfeldt T, et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA[J]. Cell Stem Cell, 2010, 7:618-630. doi:  10.1016/j.stem.2010.08.012
    [35] Miyoshi N, Ishii H, Nagano H, et al. Reprogramming of mouse and human cells to pluripotency using mature microRNAs[J]. Cell Stem Cell, 2011, 8:633-638. doi:  10.1016/j.stem.2011.05.001
    [36] Kwart D, Paquet D, Teo S, et al. Precise and efficient scarless genome editing in stem cells using CORRECT[J]. Nat Protoc, 2017, 12:329-354. doi:  10.1038/nprot.2016.171
    [37] Park CY, Sung JJ, Choi SH, et al. Modeling and correction of structural variations in patient-derived iPSCs using CRISPR/Cas9[J]. Nat Protoc, 2016, 11:2154-2169. doi:  10.1038/nprot.2016.129
    [38] Paquet D, Kwart D, Chen A, et al. Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9[J]. Nature, 2016, 533:125-129. doi:  10.1038/nature17664
    [39] Zhang Y, Schmid B, Nielsen TT, et al. Generation of a human induced pluripotent stem cell line via CRISPR-Cas9 mediated integration of a site-specific heterozygous mutation in CHMP2B[J]. Stem Cell Res, 2016, 17:148-150. doi:  10.1016/j.scr.2016.06.004
    [40] Hockemeyer D, Jaenisch R. Induced pluripotent stem cells meet genome editing[J]. Cell Stem Cell, 2016, 18:573-586. doi:  10.1016/j.stem.2016.04.013
    [41] Suh W. A new era of disease modeling and drug discovery using induced pluripotent stem cells[J]. Arch Pharm Res, 2017, 40:1-12. doi:  10.1007/s12272-016-0871-0
    [42] Maetzel D, Sarkar S, Wang H, et al. Genetic and chemical correction of cholesterol accumulation and impaired autophagy in hepatic and neural cells derived from Niemann-Pick Type C patient-specific iPS cells[J]. Stem Cell Reports, 2014, 2:866-880. doi:  10.1016/j.stemcr.2014.03.014
    [43] Hall CE, Yao Z, Choi M, et al. Progressive motor neuron pathology and the role of astrocytes in a human stem cell model of VCP-related ALS[J]. Cell Rep, 2017, 19:1739-1749. doi:  10.1016/j.celrep.2017.05.024
    [44] Yoshida M, Kitaoka S, Egawa N, et al. Modeling the early phenotype at the neuromuscular junction of spinal muscular atrophy using patient-derived iPSCs[J]. Stem Cell Reports, 2015, 4:561-568. doi:  10.1016/j.stemcr.2015.02.010
    [45] Okuno H, Renault Mihara F, Ohta S, et al. CHARGE syndrome modeling using patient-iPSCs reveals defective migra-tion of neural crest cells harboring CHD7 mutations[J]. Elife, 2017, 6. http://www.ncbi.nlm.nih.gov/pubmed/29179815
    [46] Chailangkarn T, Muotri AR. Modeling Williams syndrome with induced pluripotent stem cells[J]. Neurogenesis, 2017, 4:e1283187. doi:  10.1080/23262133.2017.1283187
    [47] Aflaki E, Borger DK, Moaven N, et al. A new glucocerebrosidase chaperone reduces alpha-synuclein and glycolipid levels in iPSC-derived dopaminergic neurons from patients with Gaucher disease and Parkinsonism[J]. J Neurosci, 2016, 36:7441-7452. doi:  10.1523/JNEUROSCI.0636-16.2016
    [48] Awad O, Sarkar C, Panicker LM, et al. Altered TFEB-mediated lysosomal biogenesis in Gaucher disease iPSC-derived neuronal cells[J]. Hum Mol Genet, 2015, 24:5775-5788. doi:  10.1093/hmg/ddv297
    [49] Chou SJ, Yu WC, Chang YL, et al. Energy utilization of induced pluripotent stem cell-derived cardiomyocyte in Fabry disease[J]. Int J Cardiol, 2017, 232:255-263. doi:  10.1016/j.ijcard.2017.01.009
    [50] Sato Y, Kobayashi H, Higuchi T, et al. TFEB overexpression promotes glycogen clearance of Pompe disease iPSC-derived skeletal muscle[J]. Mol Ther Methods Clin Dev, 2016, 3:16054. doi:  10.1038/mtm.2016.54
    [51] Yoshida S, Nakanishi C, Okada H, et al. Characteristics of induced pluripotent stem cells from clinically divergent female monozygotic twins with Danon disease[J]. J Mol Cell Cardiol, 2017, 114:234-242. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=daf07d986399625d5b7630c36765db78
    [52] HD iPSC Consortium. Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice[J]. Nat Neurosci, 2017, 20:648-660. doi:  10.1038/nn.4532
    [53] Lukovic D, Artero Castro A, Delgado AB, et al. Human iPSC derived disease model of MERTK-associated retinitis pigmentosa[J]. Sci Rep, 2015, 5:12910. doi:  10.1038/srep12910
    [54] Ramsden CM, Nommiste B, A RL, et al. Rescue of the MERTK phagocytic defect in a human iPSC disease model using translational read-through inducing drugs[J]. Sci Rep, 2017, 7:51. doi:  10.1038/s41598-017-00142-7
    [55] Matsumoto Y, Ikeya M, Hino K, et al. New protocol to optimize iPS cells for genome analysis of fibrodysplasia ossificans progressiva[J]. Stem Cells, 2015, 33:1730-1742. doi:  10.1002/stem.1981
    [56] Barruet E, Morales BM, Lwin W, et al. The ACVR1 R206H mutation found in fibrodysplasia ossificans progressiva increases human induced pluripotent stem cell-derived endothelial cell formation and collagen production through BMP-mediated SMAD1/5/8 signaling[J]. Stem Cell Res Ther, 2016, 7:115. doi:  10.1186/s13287-016-0372-6
    [57] Yi F, Qu J, Li M, et al. Establishment of hepatic and neural differentiation platforms of Wilson's disease specific induced pluripotent stem cells[J]. Protein Cell, 2012, 3:855-863. doi:  10.1007/s13238-012-2064-z
    [58] Granata A, Serrano F, Bernard WG, et al. An iPSC-derived vascular model of Marfan syndrome identifies key mediators of smooth muscle cell death[J]. Nat Genet, 2017, 49:97-109. doi:  10.1038/ng.3723
    [59] Park JW, Yan L, Stoddard C, et al. Recapitulating and correcting Marfan syndrome in a cellular model[J]. Int J Biol Sci, 2017, 13:588-603. doi:  10.7150/ijbs.19517
    [60] Fink JJ, Robinson TM, Germain ND, et al. Disrupted neuronal maturation in Angelman syndrome-derived induced pluripotent stem cells[J]. Nat Commun, 2017, 8:15038. doi:  10.1038/ncomms15038
    [61] Francis KR, Ton AN, Xin Y, et al. Modeling Smith-Lemli-Opitz syndrome with induced pluripotent stem cells reveals a causal role for Wnt/beta-catenin defects in neuronal choles-terol synthesis phenotypes[J]. Nat Med, 2016, 22:388-396. doi:  10.1038/nm.4067
    [62] Ebert AD, Yu J, Rose FF Jr, et al. Induced pluripotent stem cells from a spinal muscular atrophy patient[J]. Nature, 2009, 457:277-280. doi:  10.1038/nature07677
    [63] Itzhaki I, Maizels L, Huber I, et al. Modelling the long QT syndrome with induced pluripotent stem cells[J]. Nature, 2011, 471:225-259. doi:  10.1038/nature09747
    [64] Carlessi L, Fusar Poli E, Bechi G, et al. Functional and molecular defects of hiPSC-derived neurons from patients with ATM deficiency[J]. Cell Death Dis, 2014, 5:e1342. doi:  10.1038/cddis.2014.310
    [65] Long Y, Xu M, Li R, et al. Induced pluripotent stem cells for disease modeling and evaluation of therapeutics for Niemann-Pick disease type A[J]. Stem Cells Transl Med, 2016, 5:1644-1655. doi:  10.5966/sctm.2015-0373
    [66] Trilck M, Hubner R, Seibler P, et al. Niemann-Pick type C1 patient-specific induced pluripotent stem cells display disease specific hallmarks[J]. Orphanet J Rare Dis, 2013, 8:144. doi:  10.1186/1750-1172-8-144
    [67] Vessoni AT, Herai RH, Karpiak JV, et al. Cockayne syndrome-derived neurons display reduced synapse density and altered neural network synchrony[J]. Hum Mol Genet, 2016, 25:1271-1280. doi:  10.1093/hmg/ddw008
    [68] Bell S, Peng H, Crapper L, et al. A rapid pipeline to model rare neurodevelopmental disorders with simultaneous CRISPR/Cas9 gene editing[J]. Stem Cells Transl Med, 2017, 6:886-896. doi:  10.1002/sctm.16-0158
    [69] Munsat TL, Davies KE. International SMA consortium meeting[J]. Neuromuscul Disord, 1992, 2:423-428. doi:  10.1016/S0960-8966(06)80015-5
    [70] DeRosa BA, Van Baaren JM, Dubey GK, et al. Derivation of autism spectrum disorder-specific induced pluripotent stem cells from peripheral blood mononuclear cells[J]. Neurosci Lett, 2012, 516:9-14. doi:  10.1016/j.neulet.2012.02.086
    [71] Marchetto MC, Belinson H, Tian Y, et al. Altered proli-feration and networks in neural cells derived from idiopathic autistic individuals[J]. Mol Psychiatry, 2017, 22:820-835. doi:  10.1038/mp.2016.95
    [72] Ciucci F, Putignano E, Baroncelli L, et al. Insulin-like growth factor 1(IGF-1) mediates the effects of enriched environment (EE) on visual cortical development[J]. PLoS One, 2007, 2:e475. doi:  10.1371/journal.pone.0000475
    [73] Cheng CM, Reinhardt RR, Lee WH, et al. Insulin-like growth factor 1 regulates developing brain glucose metabolism[J]. Proc Natl Acad Sci USA, 2000, 97:10236-10241. doi:  10.1073/pnas.170008497
    [74] Studer L, Vera E, Cornacchia D. Programming and reprogramming cellular age in the era of induced pluripotency[J]. Cell Stem Cell, 2015, 16:591-600. doi:  10.1016/j.stem.2015.05.004
    [75] Miller JD, Ganat YM, Kishinevsky S, et al. Human iPSC-based modeling of late-onset disease via progerin-induced aging[J]. Cell Stem Cell, 2013, 13:691-705. doi:  10.1016/j.stem.2013.11.006
    [76] Cooper O, Seo H, Andrabi S, et al. Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease[J]. Sci Transl Med, 2012, 4:141ra90. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=0891cbbc6cb59992619f9477ee7f7171
    [77] Pearson BL, Simon JM. Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration[J]. Nat Commun, 2016, 7:11173. doi:  10.1038/ncomms11173
    [78] Nguyen HN, Byers B, Cord B, et al. LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress[J]. Cell Stem Cell, 2011, 8:267-280. doi:  10.1016/j.stem.2011.01.013
    [79] Vera E, Bosco N, Studer L. Generating late-onset human iPSC-based disease models by inducing neuronal age-related phenotypes through telomerase manipulation[J]. Cell Rep, 2016, 17:1184-1192. doi:  10.1016/j.celrep.2016.09.062
    [80] Liu GH, Barkho BZ, Ruiz S, et al. Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome[J]. Nature, 2011, 472:221-225. doi:  10.1038/nature09879
    [81] Lancaster MA, Knoblich JA. Organogenesis in a dish:modeling development and disease using organoid technologies[J]. Science, 2014, 345:1247125. doi:  10.1126/science.1247125
    [82] Camp JG, Badsha F, Florio M, et al. Human cerebral organoids recapitulate gene expression programs of fetal neocor-tex development[J]. Proc Natl Acad Sci USA, 2015, 112:15672-15677. doi:  10.1073/pnas.1520760112
    [83] Otani T, Marchetto MC, Gage FH, et al. 2D and 3D stem cell models of primate cortical development identify species-specific differences in progenitor behavior contributing to brain size[J]. Cell Stem Cell, 2016, 18:467-480. doi:  10.1016/j.stem.2016.03.003
    [84] Takasato M, Er PX, Chiu HS, et al. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis[J]. Nature, 2015, 526:564-568. doi:  10.1038/nature15695
    [85] Fatehullah A, Tan SH, Barker N. Organoids as an in vitro model of human development and disease[J]. Nat Cell Biol, 2016, 18:246-254. doi:  10.1038/ncb3312
    [86] Lee G, Ramirez CN, Kim H, et al. Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression[J]. Nat Biotechnol, 2012, 30:1244-1248. doi:  10.1038/nbt.2435
    [87] Choi SM, Kim Y, Shim JS, et al. Efficient drug screening and gene correction for treating liver disease using patient-specific stem cells[J]. Hepatology, 2013, 57:2458-2468. doi:  10.1002/hep.26237
    [88] Yamashita A, Morioka M, Kishi H, et al. Statin treatment rescues FGFR3 skeletal dysplasia phenotypes[J]. Nature, 2014, 513:507-511. doi:  10.1038/nature13775
    [89] DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry:New estimates of R&D costs[J]. J Health Econ, 2016, 47:20-33. doi:  10.1016/j.jhealeco.2016.01.012
    [90] Liang P, Lan F, Lee AS, et al. Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity[J]. Circulation, 2013, 127:1677-1691. doi:  10.1161/CIRCULATIONAHA.113.001883
    [91] Kimbrel EA, Lanza R. Current status of pluripotent stem cells:moving the first therapies to the clinic[J]. Nat Rev Drug Discov, 2015, 14:681-692. doi:  10.1038/nrd4738
    [92] Trounson A, DeWitt ND. Pluripotent stem cells progressing to the clinic[J]. Nat Rev Mol Cell Biol, 2016, 17:194-200. doi:  10.1038/nrm.2016.10
    [93] Pera MF. Stem cells:The dark side of induced pluripotency[J]. Nature, 2011, 471:46-47. doi:  10.1038/471046a
    [94] Thomsen GM, Gowing G, Svendsen S, et al. The past, present and future of stem cell clinical trials for ALS[J]. Exp Neurol, 2014, 262 Pt B:127-137. doi:  10.1016/j.expneurol.2014.02.021
    [95] Lee AS, Tang C, Rao MS, et al. Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies[J]. Nat Med, 2013, 19:998-1004. doi:  10.1038/nm.3267
    [96] Lee MO, Moon SH, Jeong HC, et al. Inhibition of pluripotent stem cell-derived teratoma formation by small molecules[J]. Proc Natl Acad Sci USA, 2013, 110:E3281-3290. doi:  10.1073/pnas.1303669110
    [97] Lund RJ, Narva E, Lahesmaa R. Genetic and epigenetic stability of human pluripotent stem cells[J]. Nat Rev Genet, 2012, 13:732-744. doi:  10.1038/nrg3271
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