Research Papers:

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

Eun-Ah Sung, Kyung-Rok Yu, Ji-Hee Shin, Yoojin Seo, Hyung-Sik Kim, Myung Guen Koog, Insung Kang, Jae-Jun Kim, Byung-Chul Lee, Tae-Hoon Shin, Jin Young Lee, Seunghee Lee, Tae-Wook Kang, Soon Won Choi and Kyung-Sun Kang _

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Oncotarget. 2017; 8:85428-85441. https://doi.org/10.18632/oncotarget.19976

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Eun-Ah Sung1,2,*, Kyung-Rok Yu1,2,4,*, Ji-Hee Shin1,2, Yoojin Seo1,5,6, Hyung-Sik Kim1,5,6, Myung Guen Koog1,2, Insung Kang1,2, Jae-Jun Kim1,2, Byung-Chul Lee1,2, Tae-Hoon Shin1,2, Jin Young Lee1,2, Seunghee Lee1,2,3, Tae-Wook Kang1,2,3, Soon Won Choi1,2 and Kyung-Sun Kang1,2

1Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea

2Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea

3Institute for Stem Cell and Regenerative Medicine in Kangstem Biotech, Biomedical Science Building, Seoul National University, Seoul 08826, Republic of Korea

4Current/Present address: Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA

5Current/Present address: Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea

6Current/Present address: Pusan National University School of Medicine, Busan 49241, Republic of Korea

*These authors have contributed equally to this work

Correspondence to:

Kyung-Sun Kang, email: [email protected]

Keywords: direct conversion, induced neural stem cell, niemann-pick disease type C, patient specific

Received: February 07, 2017    Accepted: July 18, 2017    Published: August 07, 2017


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 WT-iNSCs 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 NPC-iNSCs 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.

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