BNIP3 induction by hypoxia stimulates FASN-dependent free fatty acid production enhancing therapeutic potential of umbilical cord blood-derived human mesenchymal stem cells
| Autor: | So Hee Ko, Hyun Jik Lee, Sang Hun Lee, Gee Euhn Choi, Young Hyun Jung, Ho Jae Han, Sei Jung Lee |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
CM-H2DCFDA 2′ 7′-dichlorodihydrofluorescein diacetate FFA Free fatty acid FASN fatty acid synthase Clinical Biochemistry PBA 4-phenyl butyric acid Apoptosis Biochemistry Mice MAGL monoacylglycerol lipase DGAT1 diglyceride acyltransferase 1 Mitophagy CHOP CCAAT-enhancer binding protein homologous protein Fatty acid synthase (FASN) FOXO3 forkhead box class O3 S.E.M standard error of mean Cyclic AMP Response Element-Binding Protein Hypoxia lcsh:QH301-705.5 CPT1A carnitine palmitoyltransferase 1A Caspase NAC N-acetyl-L-cysteine Mesenchymal stem cell lcsh:R5-920 UCB-hMSCs umbilical cord blood-derived hMSCs HNA human nuclear antigen biology GPAT1 glycerol-3-phsphate acyltransferase 1 TMRE tetramethylrhodamine ethyl ester Fatty Acids Forkhead Box Protein O3 BNIP3 Bcl2/adenovirus E1B 19 kDa protein-interacting protein 3 HIF-1α hypoxia-inducible factor-1 alpha Cell Hypoxia Mitochondria Cell biology Fatty Acid Synthase Type I Fatty acid synthase HMSCs human mesenchymal stem cells Bcl2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) FOXO3 FITC fluorescein isothiocyanate Stem cell medicine.symptom Sterol Regulatory Element Binding Protein 1 lcsh:Medicine (General) Research Paper eIF-2α eukaryotic initiation factor 2 alpha PBS phosphate buffered solution Mesenchymal Stem Cell Transplantation Cell Line PI propidium iodide PA palmitic acid 03 medical and health sciences ROS reactive oxygen species TBST tris-buffered saline containing 0.1% Tween-20 mtROS mitochondrial ROS Proto-Oncogene Proteins CCCP carbonyl cyanide m-chlorophenyl hydrazine CHIP chromatin immunoprecipitation medicine Animals Humans SCD1 stearoyl-CoA desaturase 1 CBP CREB-binding protein SREBP1 sterol regulatory element binding protein 1 Wound Healing FA fatty acid FUNDC1 FUN14 domain containing 1 Organic Chemistry Membrane Proteins Mesenchymal Stem Cells Lipid metabolism Annexin V FITC-conjugated annexinV PINK1 PTEN-induced putative kinase1 Hypoxia (medical) Hypoxia-Inducible Factor 1 alpha Subunit Molecular biology BCA bicinchoninic acid NT non-targeting Oxygen 030104 developmental biology lcsh:Biology (General) biology.protein Reactive Oxygen Species |
| Zdroj: | Redox Biology, Vol 13, Iss C, Pp 426-443 (2017) Redox Biology |
| ISSN: | 2213-2317 |
| DOI: | 10.1016/j.redox.2017.07.004 |
| Popis: | Mitophagy under hypoxia is an important factor for maintaining and regulating stem cell functions. We previously demonstrated that fatty acid synthase (FASN) induced by hypoxia is a critical lipid metabolic factor determining the therapeutic efficacy of umbilical cord blood-derived human mesenchymal stem cells (UCB-hMSCs). Therefore, we investigated the mechanism of a major mitophagy regulator controlling lipid metabolism and therapeutic potential of UCB-hMSCs. This study revealed that Bcl2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)-dependent mitophagy is important for reducing mitochondrial reactive oxygen species accumulation, anti-apoptosis, and migration under hypoxia. And, BNIP3 expression was regulated by CREB binding protein-mediated transcriptional actions of HIF-1α and FOXO3. Silencing of BNIP3 suppressed free fatty acid (FFA) synthesis regulated by SREBP1/FASN pathway, which is involved in UCB-hMSC apoptosis via caspases cleavage and migration via cofilin-1-mediated F-actin reorganization in hypoxia. Moreover, reduced mouse skin wound-healing capacity of UCB-hMSC with hypoxia pretreatment by BNIP3 silencing was recovered by palmitic acid. Collectively, our findings suggest that BNIP3-mediated mitophagy under hypoxia leads to FASN-induced FFA synthesis, which is critical for therapeutic potential of UCB-hMSCs with hypoxia pretreatment. Graphical abstract fx1 Highlights • BNIP3 induction by hypoxia mainly controls mitophagy and mitochondrial ROS production in UCB-hMSCs. • BNIP3 silencing impairs UCB-hMSC functions such as survival, migration and free fatty acid production under hypoxia. • BNIP3 silencing suppresses SREBP1/FASN-mediated free fatty acid production via ROS regulation under hypoxia. • BNIP3 silencing decreased skin wound healing potential of hypoxia-pretreated UCB-hMSCs. • Palmitic acid addition recovers decreased therapeutic potential of UCB-hMSCs by BNIP3 silencing. |
| Databáze: | OpenAIRE |
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