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.
Highlights
Introduction NiemannPick type C (NPC) disease is an inherited lipid storage disorder, with an estimated incidence of 1:20,000 to 1:150,000 live births
In this study, we have explored the non-invasive strategy of intranasally delivering hUCB-mesenchymal stem cells (MSCs) to treat Niemann–Pick type C1 (NPC1) disease
The intranasal delivery of hUCB-MSCs increased the motor function of NPC1mutant mice, and this phenomenon may be explained by the increased Purkinje cell survival
Summary
Pick type C (NPC) disease is an inherited lipid storage disorder, with an estimated incidence of 1:20,000 to 1:150,000 live births. The dysfunction of NPC proteins leads to a defect in intercellular cholesterol trafficking, characterized by the impaired exit of cholesterol from late endosomes/lysosomes (LE/L)[2]. Purkinje cells is one of the primary indicators of NPC, which results in the development of several neuromuscular symptoms, such as ataxia, dysarthria, and dysphagia, during growth[3]. The excessive accumulation of cholesterol in endolysosomes is considered to be a major pathogenic mechanism of NPC disease[4]. Several strategies to reduce cholesterol levels in NPC disease treatment have been attempted. NPC1-mutant mice treated with hydroxypropyl-β-cyclodextrin in primary cultures of neurons and glial cells had significantly improved levels of Official journal of the Korean Society for Biochemistry and Molecular Biology
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