Stem cell-secreted 14,15- epoxyeicosatrienoic acid rescues cholesterol homeostasis and autophagic flux in Niemann–Pick-type C disease

• Published in: Experimental & molecular medicine Vol. 50; no. 11; pp. 1 - 14
• Main Authors: Kang, Insung, Lee, Byung-Chul, Lee, Jin Young, Kim, Jae-Jun, Sung, Eun-Ah, Lee, Seung Eun, Shin, Nari, Choi, Soon Won, Seo, Yoojin, Kim, Hyung-Sik, Kang, Kyung-Sun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.11.2018; Springer Nature B.V; Nature Publishing Group; 생화학분자생물학회
• Subjects: 13; 13/100; 14; 14/32; 59; 59/5; 692/308/2171; 692/699/375/364; 8,11,14-Eicosatrienoic Acid - analogs & derivatives; 8,11,14-Eicosatrienoic Acid - metabolism; 82; 82/1; Animals; Astrocytes; Autophagy; Biomedical and Life Sciences; Biomedicine; Brain diseases; Cells, Cultured; Cerebellum; Cholesterol; Cholesterol - metabolism; Cord blood; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450; Dentate gyrus; Fibroblasts; Genetic disorders; Granule cells; Homeostasis; Humans; Intranasal administration; Medical Biochemistry; Mesenchymal Stem Cell Transplantation - methods; Mesenchymal Stem Cells - metabolism; Mesenchyme; Metabolic disorders; Mice; Mice, Inbred BALB C; Microglia; Molecular Medicine; Niemann-Pick Disease, Type C - metabolism; Niemann-Pick Disease, Type C - therapy; Npc1 protein; Patients; Phagocytosis; Purkinje cells; Purkinje Cells - metabolism; Rodents; Stem cell transplantation; Stem Cells; Umbilical cord; 생화학
• ISSN: 1226-3613; 2092-6413; 2092-6413
• DOI: 10.1038/s12276-018-0176-0

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. Inherited metabolic disease: Restoring motor function by reducing cholesterol An acid secreted by stem cells can reduce the excess cholesterol caused by a genetic metabolic disorder. Niemann–Pick type C disease is a rare, inherited condition that causes defective muscular development and progressive neurological degeneration. A key disease mechanism is the excessive accumulation of cholesterol within cells. Kyung-Sun Kang at Seoul National University, South Korea, and co-workers have demonstrated that a metabolite molecule called 14,15-epoxyeicosatrienoic acid (14,15-EET) derived from stem cells from human umbilical cord blood significantly reduced cholesterol in Neimann-Pick Type C mouse models and human cell samples. The team administered the stem cell therapy non-invasively via the nose, and observed significant improvements in motor function in the mice. Experiments in both animals and cells showed that the treatment resulted in reduced cholesterol levels and the correction of defective signalling within cells.