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

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.