WAS综合征特异性无整合诱导性多能干细胞体外造血分化及基因靶向编辑研究
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摘要
细胞重编程技术的重大突破为研究人类发育和疾病搭建了新的体外平台,更为个体化细胞治疗提供了新的策略,是发育生物学领域的巨大革新。解决安全性问题是重编程细胞走向临床应用的前提和关键。本研究利用游离型载体技术将WAS综合征(Wiskott-Aldrich Syndrome, WAS)患者的成纤维细胞重编程为安全的无整合诱导性多能干细胞(Induced Pluripotent Stem Cell, iPSCs)。这些WAS特异性iPSCs可在体外诱导分化为血液细胞,并显示疾病相关表型,因此可作为WAS的体外研究平台。更为重要的是,我们对TALEN介导的WAS基因同源重组策略进行了优化,可对iPSCs基因组高效编辑,从而得到纠正WAS基因的患者特异性iPSCs本研究将为再生医学替代细胞iPSCs的安全获得和安全基因操作提供典范。
第一章WAS综合征特异性无整合诱导性多能干细胞株的建立和鉴定
WAS综合征是由WAS基因发生功能缺失型突变所导致的x染色体连锁的免疫缺陷病。WAS蛋白在血液细胞中特异性表达并介导Actin多聚化,是维持正常免疫系统功能不可或缺的重要因子。为建立WAS综合征的体外研究模型,我们利用表达OCT3/4、SOX2、KLF4、L-MYC、LIN28和TP53shRNA的游离型载体重编程WAS综合征患者成纤维细胞。我们所建立的WAS综合征特异性iPSCs (WAS-iPSCs)在形态学与基因表达模式上均与正常人胚胎干细胞(Embryonic Stem Cells, ESCs)相似,且表达完全重编程特异性标志Tra-1-60和Tra-1-81。PCR分析和基因测序结果显示这些WAS-iPSC克隆不含任何重编程载体DNA残留,且均携带患者WAS基因突变,为安全无整合的iPSCs,可用作体外疾病模拟及后续基因操作。
第二章WAS-iPSCs体外造血分化及疾病表型鉴定
iPSCs的体外定向分化为研究正常生理发育及疾病进展创造了体外研究平台。为了证实WAS综合征疾病相关表型可在体外模拟,我们利用基质细胞共培养法诱导WAS-iPSCs造血分化。在GM-CSF和M-CSF的作用下,我们从分化体系中成功分离并扩增了CD45+CD43+CD11c+造血祖细胞,后者可在甲基纤维素培养基中分化形成CFU-G、CFU-M和CFU-GM等集落形成单位。为研究成熟免疫细胞功能,我们利用相关细胞因子进一步分化得到CD11c+CD14+CD163+巨噬细胞。我们通过体外实验证实WAS-iPSCs来源的巨噬细胞具有抗原摄取与处理能力、吞噬作用、趋化作用等巨噬细胞经典生物学行为。同时,我们通过免疫荧光染色观察到WAS-iPSCs来源的巨噬细胞由于WAS蛋白功能不全所导致的足体结构形成缺陷。综上,本研究所建立的WAS-iPSCs克隆为研究WAS蛋白在血液免疫系统发育过程中的作用提供了理想的体外模型,经过基因纠正后,将为WAS综合征患者的干细胞基因治疗提供无限细胞来源。
‘第三章TALEN介导的WAS基因高效靶向编辑
对患者来源iPSCs的病变基因进行安全高效的修复是个体化干细胞基因治疗的关键。转录激活子样效应因子核酸酶(Transcription Activator-Like Effector Nuclease, TALEN)介导的基因靶向编辑是目前哺乳动物基因组改造最有前景的策略之一。但是,TALEN的优化设计方案、以及TALEN表达质粒与基因编辑模板的细胞导入方案还没有很好地建立。因此TALEN介导的基因靶向编辑效率普遍较低。本研究针对WAS基因6号内含子高突变位点设计了一系列TALEN组合,并探讨了TALEN靶序列和spacer长度对靶向基因剪切效率的影响,从而优化了TALEN的设计方案。同时,我们采用整合酶缺陷型慢病毒载体(Integration-defective Lentiviral Vectors, IDLVs)作为基因编辑模板的导入手段,使TALEN介导的靶向基因编辑效率大幅提高。本研究为实现人iPSCs的高效基因改造提供了新的优化策略。
Progress in cell reprogramming revolutionizes the whole field of development biology, provides unprecedented opportunity for ex vivo study of human diseases and opens up innovative personalized cell therapy strategy to treat these diseases. Safety concern is one of the most important issues for the clinical application of those reprogrammed cells. Here we show that integration-free induced pluripotent stem cell (iPSCs) can be generated from the fibroblasts of a Wiskott-Aldrich Syndrome (WAS) patient. Those WAS-iPSCs give rise to hematopoietic cells when being differentiated in vitro, and show disease related phenotypes. Most importantly, we show the possibility that the WAS gene mutation in WAS-iPSCs can be corrected via an enhanced TALEN mediated homologous recombination strategy. Our work offers proof-of-principle that iPSCs can be generated and manipulated safely in vitro and serve as an alternative sauce for regenerative medicine.
Chapter1Establishment and characterization of integration-free iPSCs from WAS patient fibroblasts
WAS is an X-linked primary immunodeficiency disorder caused by loss-of-function mutations in the gene for the WAS protein. WAS protein is exclusively expressed in hematopoietic lineages and it modulates actin polymerization which is indispensable for the development of an organized immunological system for host defense and maintenance of tolerance. To establish an ex vivo model to study WAS, we reprogrammed the fibroblasts of a WAS patient with3episomal plasmids expressing OCT3/4, SOX2, KLF4, L-MYC, LIN28and TP53shRNA. The established iPSC clones exhibited similar morphology and gene expression pattern as normal human embryonic stem cells (ESCs), and expressed pluripotency markers including Tra-1-60and Tra-1-81. PCR analysis of four WAS-iPSC clones failed to detect any residual episomal DNA, confirming the loss of the input plasmids once the iPSC clones were established. The WAS gene mutation in parental fibroblasts was inherited by all the iPSC clones we tested, indicating those WAS-iPSC clones could be used for in vitro disease modeling and gene manipulation.
Chapter2Hematopoietic differentiation of WAS patient-specific iPSCs shows distinct disease related phenotypes
In vitro differentiation of iPSCs to specific tissues or cell types facilitates the study of normal development and disease progression. To determine whether the WAS disease phenotypes can be recapitulated in a dish, we differentiated the WAS-iPSCs into hematopoietic lineage ex vivo through a stromal cell co-culture system. In the presence of GM-CSF and M-CSF, we successfully expanded CD45+CD43+CD11c+progenitors which could give rise to CFU-G, CFU-M and CFU-GM in colony forming cell assay. Further differentiation with proper cytokines showed normal maturation of those progenitors into CD11c+CD14+CD163+macrophages, the vital cell population of innate and adaptive immunity. The WAS-iPSCs derived macrophages were functional in antigen uptake and processing, phagocytosis and chemotaxis. However, these macrophages failed to show the normal podosome formation, due to the defect in WAS gene. Thus these WAS-iPSC clones may provide an ideal ex vivo system to study the role of WAS protein in the development of a functional immune system, and provide a safer, unlimited source for stem cell gene therapy for WAS patients upon gene correction.
Chapter3High efficiency TALEN-based WAS gene editing mediated by an integration defective lentiviral vector
Safely and efficiently correction of mutant genes in patient specific iPSCs is crucial for personalized stem cell gene therapy. Recent development in the design of Transcription Activator-Like Effector Nuclease (TALEN) provides a new strategy for targeted gene editing. However, the guideline to optimize TALEN design and the strategy for the delivery of TALEN and the gene editing template are not fully established, and the gene editing efficiency in mammalian cells especially in human iPSCs remains low. In the current study, we designed several TALEN pairs targeting a region in intron6of the WAS gene and showed that both the number of the TALEN repeats and the size of the spacer between the two TALEN-binding sites could modulate the genomic cutting efficiency. We also found that using an integration-defective lentiviral vector (IDLV) to deliver the gene-editing template significantly enhanced the gene editing efficiency. Our study not only showed a possible effective way to achieve WAS gene correction in the WAS-iPSC clones we established, but also facilitate the use of TALEN as a tool for potent genome editing in mammalian cells such as human iPSCs.
第一章WAS综合征特异性无整合诱导性多能干细胞株的建立和鉴定
WAS综合征是由WAS基因发生功能缺失型突变所导致的x染色体连锁的免疫缺陷病。WAS蛋白在血液细胞中特异性表达并介导Actin多聚化,是维持正常免疫系统功能不可或缺的重要因子。为建立WAS综合征的体外研究模型,我们利用表达OCT3/4、SOX2、KLF4、L-MYC、LIN28和TP53shRNA的游离型载体重编程WAS综合征患者成纤维细胞。我们所建立的WAS综合征特异性iPSCs (WAS-iPSCs)在形态学与基因表达模式上均与正常人胚胎干细胞(Embryonic Stem Cells, ESCs)相似,且表达完全重编程特异性标志Tra-1-60和Tra-1-81。PCR分析和基因测序结果显示这些WAS-iPSC克隆不含任何重编程载体DNA残留,且均携带患者WAS基因突变,为安全无整合的iPSCs,可用作体外疾病模拟及后续基因操作。
第二章WAS-iPSCs体外造血分化及疾病表型鉴定
iPSCs的体外定向分化为研究正常生理发育及疾病进展创造了体外研究平台。为了证实WAS综合征疾病相关表型可在体外模拟,我们利用基质细胞共培养法诱导WAS-iPSCs造血分化。在GM-CSF和M-CSF的作用下,我们从分化体系中成功分离并扩增了CD45+CD43+CD11c+造血祖细胞,后者可在甲基纤维素培养基中分化形成CFU-G、CFU-M和CFU-GM等集落形成单位。为研究成熟免疫细胞功能,我们利用相关细胞因子进一步分化得到CD11c+CD14+CD163+巨噬细胞。我们通过体外实验证实WAS-iPSCs来源的巨噬细胞具有抗原摄取与处理能力、吞噬作用、趋化作用等巨噬细胞经典生物学行为。同时,我们通过免疫荧光染色观察到WAS-iPSCs来源的巨噬细胞由于WAS蛋白功能不全所导致的足体结构形成缺陷。综上,本研究所建立的WAS-iPSCs克隆为研究WAS蛋白在血液免疫系统发育过程中的作用提供了理想的体外模型,经过基因纠正后,将为WAS综合征患者的干细胞基因治疗提供无限细胞来源。
‘第三章TALEN介导的WAS基因高效靶向编辑
对患者来源iPSCs的病变基因进行安全高效的修复是个体化干细胞基因治疗的关键。转录激活子样效应因子核酸酶(Transcription Activator-Like Effector Nuclease, TALEN)介导的基因靶向编辑是目前哺乳动物基因组改造最有前景的策略之一。但是,TALEN的优化设计方案、以及TALEN表达质粒与基因编辑模板的细胞导入方案还没有很好地建立。因此TALEN介导的基因靶向编辑效率普遍较低。本研究针对WAS基因6号内含子高突变位点设计了一系列TALEN组合,并探讨了TALEN靶序列和spacer长度对靶向基因剪切效率的影响,从而优化了TALEN的设计方案。同时,我们采用整合酶缺陷型慢病毒载体(Integration-defective Lentiviral Vectors, IDLVs)作为基因编辑模板的导入手段,使TALEN介导的靶向基因编辑效率大幅提高。本研究为实现人iPSCs的高效基因改造提供了新的优化策略。
Progress in cell reprogramming revolutionizes the whole field of development biology, provides unprecedented opportunity for ex vivo study of human diseases and opens up innovative personalized cell therapy strategy to treat these diseases. Safety concern is one of the most important issues for the clinical application of those reprogrammed cells. Here we show that integration-free induced pluripotent stem cell (iPSCs) can be generated from the fibroblasts of a Wiskott-Aldrich Syndrome (WAS) patient. Those WAS-iPSCs give rise to hematopoietic cells when being differentiated in vitro, and show disease related phenotypes. Most importantly, we show the possibility that the WAS gene mutation in WAS-iPSCs can be corrected via an enhanced TALEN mediated homologous recombination strategy. Our work offers proof-of-principle that iPSCs can be generated and manipulated safely in vitro and serve as an alternative sauce for regenerative medicine.
Chapter1Establishment and characterization of integration-free iPSCs from WAS patient fibroblasts
WAS is an X-linked primary immunodeficiency disorder caused by loss-of-function mutations in the gene for the WAS protein. WAS protein is exclusively expressed in hematopoietic lineages and it modulates actin polymerization which is indispensable for the development of an organized immunological system for host defense and maintenance of tolerance. To establish an ex vivo model to study WAS, we reprogrammed the fibroblasts of a WAS patient with3episomal plasmids expressing OCT3/4, SOX2, KLF4, L-MYC, LIN28and TP53shRNA. The established iPSC clones exhibited similar morphology and gene expression pattern as normal human embryonic stem cells (ESCs), and expressed pluripotency markers including Tra-1-60and Tra-1-81. PCR analysis of four WAS-iPSC clones failed to detect any residual episomal DNA, confirming the loss of the input plasmids once the iPSC clones were established. The WAS gene mutation in parental fibroblasts was inherited by all the iPSC clones we tested, indicating those WAS-iPSC clones could be used for in vitro disease modeling and gene manipulation.
Chapter2Hematopoietic differentiation of WAS patient-specific iPSCs shows distinct disease related phenotypes
In vitro differentiation of iPSCs to specific tissues or cell types facilitates the study of normal development and disease progression. To determine whether the WAS disease phenotypes can be recapitulated in a dish, we differentiated the WAS-iPSCs into hematopoietic lineage ex vivo through a stromal cell co-culture system. In the presence of GM-CSF and M-CSF, we successfully expanded CD45+CD43+CD11c+progenitors which could give rise to CFU-G, CFU-M and CFU-GM in colony forming cell assay. Further differentiation with proper cytokines showed normal maturation of those progenitors into CD11c+CD14+CD163+macrophages, the vital cell population of innate and adaptive immunity. The WAS-iPSCs derived macrophages were functional in antigen uptake and processing, phagocytosis and chemotaxis. However, these macrophages failed to show the normal podosome formation, due to the defect in WAS gene. Thus these WAS-iPSC clones may provide an ideal ex vivo system to study the role of WAS protein in the development of a functional immune system, and provide a safer, unlimited source for stem cell gene therapy for WAS patients upon gene correction.
Chapter3High efficiency TALEN-based WAS gene editing mediated by an integration defective lentiviral vector
Safely and efficiently correction of mutant genes in patient specific iPSCs is crucial for personalized stem cell gene therapy. Recent development in the design of Transcription Activator-Like Effector Nuclease (TALEN) provides a new strategy for targeted gene editing. However, the guideline to optimize TALEN design and the strategy for the delivery of TALEN and the gene editing template are not fully established, and the gene editing efficiency in mammalian cells especially in human iPSCs remains low. In the current study, we designed several TALEN pairs targeting a region in intron6of the WAS gene and showed that both the number of the TALEN repeats and the size of the spacer between the two TALEN-binding sites could modulate the genomic cutting efficiency. We also found that using an integration-defective lentiviral vector (IDLV) to deliver the gene-editing template significantly enhanced the gene editing efficiency. Our study not only showed a possible effective way to achieve WAS gene correction in the WAS-iPSC clones we established, but also facilitate the use of TALEN as a tool for potent genome editing in mammalian cells such as human iPSCs.
引文
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