Soga Minami, Ishitsuka Yoichi, Hamasaki Makoto, Yoneda Kaori, Furuya Hirokazu, Matsuo Muneaki, Ihn Hironobu, Fusaki Noemi, Nakamura Kimitoshi, Nakagata Naomi, Endo Fumio, Irie Tetsumi, Era Takumi
Department of Cell Modulation, Institute of Molecular Embryology and Genetics.
Stem Cells. 2015 Apr;33(4):1075-88. doi: 10.1002/stem.1917.
Niemann-Pick disease type C (NPC) is a lysosomal storage disease characterized by abnormal accumulation of free cholesterol and glycolipids. Here, we established induced pluripotent stem cell (iPSC) lines from NPC patients. Hepatocyte-like cells (HLCs) and neural progenitors derived from the iPSC lines accumulated cholesterol and displayed impaired autophagy and ATP production. A molecular signature related to lipid metabolism was also impaired in the NPC-iPSC-derived HLCs. These findings indicate that iPSC-derived cells can phenocopy human NPC. We also newly found that 2-hydroxypropyl-γ-cyclodextrin (HPGCD) could reduce the cholesterol accumulation and restore the functional and molecular abnormalities in the NPC patient-derived cells, and do so more effectively than 2-hydroxypropyl-β-cyclodextrin treatment. In addition, NPC model mice showed an improved liver status and prolonged survival with HPGCDs. Thus, iPSC lines derived from patient cells are powerful tools to study cellular models of NPC, and HPGCD is a potential new drug candidate for future treatment of this disease.
尼曼-匹克C型病（NPC）是一种溶酶体贮积病，其特征是游离胆固醇和糖脂异常蓄积。在此，我们从NPC患者中建立了诱导多能干细胞（iPSC）系。源自这些iPSC系的肝细胞样细胞（HLC）和神经祖细胞蓄积胆固醇，并表现出自噬受损和ATP生成受损。在源自NPC-iPSC的HLC中，与脂质代谢相关的分子特征也受损。这些发现表明，源自iPSC的细胞可模拟人类NPC。我们还新发现，2-羟丙基-γ-环糊精（HPGCD）可减少NPC患者来源细胞中的胆固醇蓄积，并恢复其功能和分子异常，且比2-羟丙基-β-环糊精治疗更有效。此外，NPC模型小鼠使用HPGCD后肝脏状态改善，生存期延长。因此，源自患者细胞的iPSC系是研究NPC细胞模型的有力工具，而HPGCD是未来治疗该疾病的潜在新药候选物。
