Experimental and Molecular Medicine

Korean Society for Biochemistry and Molecular Biongy (생화학분자생물학회)
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Stem cell-secreted 14,15-epoxyeicosatrienoic acid rescues cholesterol homeostasis and autophagic flux in Niemann-Pick-type C disease

  • Kang, Insung (Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University) ;
  • Lee, Byung-Chul (Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University) ;
  • Lee, Jin Young (Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University) ;
  • Kim, Jae-Jun (Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University) ;
  • Sung, Eun-Ah (Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University) ;
  • Lee, Seung Eun (Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University) ;
  • Shin, Nari (Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University) ;
  • Choi, Soon Won (Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University) ;
  • Seo, Yoojin (Biomedical Research Institute, Pusan National University School of Medicine, Pusan National University Hospital) ;
  • Kim, Hyung-Sik (Biomedical Research Institute, Pusan National University School of Medicine, Pusan National University Hospital) ;
  • Kang, Kyung-Sun (Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University)
  • Received : 2018.04.03
  • Accepted : 2018.07.18
  • Published : 2018.11.30
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Abstract

We previously demonstrated that the direct transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) into the dentate gyrus ameliorated the neurological symptoms of Niemann-Pick type C1 (NPC1)-mutant mice. However, the clinical presentation of NPC1-mutant mice was not fully understood with a molecular mechanism. Here, we found 14,15-epoxyeicosatrienoic acid (14,15-EET), a cytochrome P450 (CYP) metabolite, from hUCB-MSCs and the cerebella of NPC1-mutant mice and investigated the functional consequence of this metabolite. Our screening of the CYP2J family indicated a dysregulation in the CYP system in a cerebellar-specific manner. Moreover, in Purkinje cells, CYP2J6 showed an elevated expression level compared to that of astrocytes, granule cells, and microglia. In this regard, we found that one CYP metabolite, 14,15-EET, acts as a key mediator in ameliorating cholesterol accumulation. In confirming this hypothesis, 14,15-EET treatment reduced the accumulation of cholesterol in human NPC1 patient-derived fibroblasts in vitro by suppressing cholesterol synthesis and ameliorating the impaired autophagic flux. We show that the reduced activity within the CYP system in the cerebellum could cause the neurological symptoms of NPC1 patients, as 14,15-EET treatment significantly rescued cholesterol accumulation and impaired autophagy. We also provide evidence that the intranasal administration of hUCB-MSCs is a highly promising alternative to traumatic surgical transplantation for NPC1 patients.

Keywords

Acknowledgement

Supported by : National Research Foundation of Korea (NRF)

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