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

被引：19

作者：

Sung, Eun-Ah ^{[1
,2
]}

Yu, Kyung-Rok ^{[1
,2
,4
]}

Shin, Ji-Hee ^{[1
,2
]}

Seo, Yoojin ^{[1
,5
,6
]}

Kim, Hyung-Sik ^{[1
,5
,6
]}

Koog, Myung Guen ^{[1
,2
]}

Kang, Insung ^{[1
,2
]}

Kim, Jae-Jun ^{[1
,2
]}

Lee, Byung-Chul ^{[1
,2
]}

Shin, Tae-Hoon ^{[1
,2
]}

Lee, Jin Young ^{[1
,2
]}

Lee, Seunghee ^{[1
,2
,3
]}

Kang, Tae-Wook ^{[1
,2
,3
]}

Choi, Soon Won ^{[1
,2
]}

Kang, Kyung-Sun ^{[1
,2
]}

机构：

[1] Seoul Natl Univ, Coll Vet Med, Adult Stem Cell Res Ctr, Seoul 08826, South Korea

[2] Seoul Natl Univ, Res Inst Vet Sci, Coll Vet Med, Seoul 08826, South Korea

[3] Seoul Natl Univ, Inst Stem Cell & Regenerat Med Kangstem Biotech, Biomed Sci Bldg, Seoul 08826, South Korea

[4] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA

[5] Pusan Natl Univ Hosp, Biomed Res Inst, Busan 49241, South Korea

[6] Pusan Natl Univ, Sch Med, Busan 49241, South Korea

来源：

ONCOTARGET | 2017年 / 8卷 / 49期

关键词：

direct conversion; induced neural stem cell; niemann-pick disease type C; patient specific; HISTONE DEACETYLASE INHIBITORS; HUMAN NEURONAL MODEL; CHOLESTEROL ACCUMULATION; DIRECT CONVERSION; MOUSE; DIFFERENTIATION; INDUCTION; AUTOPHAGY; TRANSPORT; PROGRAM;

D O I：

10.18632/oncotarget.19976

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Niemann-Pick disease type C (NPC) is a neurodegenerative and lysosomal lipid storage disorder, characterized by the abnormal accumulation of unesterified cholesterol and glycolipids, which is caused by mutations in the NPC1 genes. Here, we report the generation of human induced neural stem cells from NPC patient-derived fibroblasts (NPC-iNSCs) using only two reprogramming factors SOX2 and HMGA2 without going through the pluripotent state. NPC-iNSCs were stably expandable and differentiated into neurons, astrocytes, and oligodendrocytes. However, NPC-iNSCs displayed defects in self-renewal and neuronal differentiation accompanied by cholesterol accumulation, suggesting that NPC-iNSCs retain the main features of NPC. This study revealed that the cholesterol accumulation and the impairments in self-renewal and neuronal differentiation in NPC-iNSCs were significantly improved by valproic acid. Additionally, we demonstrated that the inhibition of cholesterol transportation by U18666A in WTiNSCs mimicked the impaired self-renewal and neuronal differentiation of NPC-iNSCs, indicating that the regulation of cholesterol homeostasis is a crucial determinant for the neurodegenerative features of NPC. Taken together, these findings suggest that NPCiNSCs can serve as an unlimited source of neural cells for pathological study or drug screening in a patient specific manner. Furthermore, this direct conversion technology might be extensively applicable for other human neurodegenerative diseases.

引用

页码：85428 / 85441

页数：14

共 48 条

[1]

[Anonymous], 2015, CELL REP

[2] Sensitivity to Lysosome-Dependent Cell Death Is Directly Regulated by Lysosomal Cholesterol Content [J].