Direct conversion of patient specific human neural stem cells from Niemann-Pick disease type C patient-derived fibroblasts

Niemann-Pick disease type C;induced neural stem cell;direct conversion;patient specific;636

수의과대학 수의학과 ;

University:서울대학교 대학원

关键词: Niemann-Pick disease type C;    induced neural stem cell;    direct conversion;    patient specific;    636;   

Others  :  http://s-space.snu.ac.kr/bitstream/10371/133750/1/000000133602.pdf

美国|英语

来源: Seoul National University Open Repository

【 摘 要 】

Niemann-Pick disease type C is a neurodegenerative and lysosomal lipid storage disorder, characterized by abnormal accumulation of unesterified cholesterol and glycolipids, which is caused by mutations in NPC1 or NPC2 genes. Here, the generation of human induced neural stem cells from NPC patient-derived fibroblasts (NPC-iNSCs) using only two reprogramming factors without going through the pluripotent state were reported. NPC-iNSC lines were stably expandable and showed trilineage neural differentiation potential. However, NPC-iNSCs displayed cholesterol accumulation, defective self-renewal, and neuronal differentiation, suggesting that NPC-iNSC lines retain main features of NPC disease. It was found that valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, significantly ameliorated the cholesterol accumulation and restored cholesterol homeostasis. Furthermore, VPA corrected the impaired self-renewal and neuronal differentiation of NPC-iNSC lines. Taken together, these findings suggest that NPC-iNSCs could provide a powerful platform for pathological study or drug screening in a patient specific manner and that this direct conversion technology may extend to other human neurodegenerative diseases.