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.
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.
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胆固醇积累的遗传和化学校正，源自Niemann-Pick型C型患者特异性IPS细胞的肝和神经细胞中自噬受损。
DOI：
10.1016/j.stemcr.2014.03.014
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发表时间：
2014-06-03
影响因子：
5.9
通讯作者：
Jaenisch, Rudolf
中科院分区：
文献类型：
--
作者：
Maetzel, Dorothea;Sarkar, Sovan;Wang, Haoyi;Abi-Mosleh, Lina;Xu, Ping;Cheng, Albert W.;Gao, Qing;Mitalipova, Maisam;Jaenisch, Rudolf
C型尼曼-匹克（NPC）病是一种致命的遗传性脂质储存障碍，可导致严重的神经变性和肝功能障碍，患者的治疗选择有限。NPC 1功能的丧失导致胆固醇代谢的缺陷，最近被认为与自噬的失调有关。在这里，我们报告了使用转录激活因子样效应核酸酶（TALEN）生成NPC患者特异性诱导多能干细胞（iPSC）的同基因对。我们观察到降低细胞活力，胆固醇积累，和功能失调的自噬通量在NPC 1缺陷的人肝细胞和神经细胞。致病突变的遗传校正挽救了这些缺陷，并将NPC 1蛋白功能与胆固醇代谢受损和自噬直接联系起来。在受疾病影响的人类细胞中筛选自噬诱导化合物显示了细胞类型特异性。研究发现卡马西平具有细胞保护作用，可有效恢复NPC 1缺陷肝细胞和神经元细胞的自噬缺陷，因此可能是一种有前途的治疗选择，对NPC疾病具有总体益处。产生尼曼-匹克C型（NPC）疾病患者特异性iPSC NPC 1肝脏和神经元细胞显示胆固醇和自噬通量的缺陷TALEN介导的遗传校正拯救胆固醇和自噬缺陷自噬诱导剂可以恢复功能性自噬并增加细胞活力iPSC对于研究受影响细胞类型的人类疾病和筛选治疗化合物是有价值的。在这里，Jaenisch及其同事表明，Niemann-Pick C型iPSCs中致病突变的遗传校正直接将NPC 1蛋白功能与胆固醇代谢受损和自噬联系起来。用卡马西平刺激自噬在肝细胞和神经细胞中都具有细胞保护作用，因此可能具有治疗意义。
Niemann-Pick type C (NPC) disease is a fatal inherited lipid storage disorder causing severe neurodegeneration and liver dysfunction with only limited treatment options for patients. Loss of NPC1 function causes defects in cholesterol metabolism and has recently been implicated in deregulation of autophagy. Here, we report the generation of isogenic pairs of NPC patient-specific induced pluripotent stem cells (iPSCs) using transcription activator-like effector nucleases (TALENs). We observed decreased cell viability, cholesterol accumulation, and dysfunctional autophagic flux in NPC1-deficient human hepatic and neural cells. Genetic correction of a disease-causing mutation rescued these defects and directly linked NPC1 protein function to impaired cholesterol metabolism and autophagy. Screening for autophagy-inducing compounds in disease-affected human cells showed cell type specificity. Carbamazepine was found to be cytoprotective and effective in restoring the autophagy defects in both NPC1-deficient hepatic and neuronal cells and therefore may be a promising treatment option with overall benefit for NPC disease. Generation of Niemann-Pick type C (NPC) disease patient-specific iPSCs NPC1 hepatic and neuronal cells show defects in cholesterol and autophagic flux TALEN-mediated genetic correction rescues the cholesterol and autophagy defects Autophagy inducers can restore functional autophagy and increase cell viability iPSCs are valuable for studying human diseases in affected cell types and screening for therapeutic compounds. Here, Jaenisch and colleagues show that genetic correction of a disease-causing mutation in Niemann-Pick type C iPSCs directly linked NPC1 protein function to impaired cholesterol metabolism and autophagy. Stimulating autophagy with carbamazepine was cytoprotective in both hepatic and neural cells and therefore may be of therapeutic relevance.
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