Abstract
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 19kDa 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.
Highlights
Metabolic alteration of stem cells under hypoxia is prerequisite to controlling stem cell function activated by oxygen signaling [1,2]
To confirm the role of Bcl2/adenovirus E1B kDa protein-interacting protein 3 (BNIP3) expression induced by hypoxia in lipid metabolism, we examined mRNA expressions of lipid metabolic enzymes including fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1), SCD5, glycerol-3-phsphate acyltransferase 1 (GPAT1), GPAT3, GPAT4, monoacylglycerol lipase (MAGL), diglyceride acyltransferase 1 (DGAT1), and carnitine palmitoyltransferase 1A (CPT1A) in UCB-human mesenchymal stem cells (hMSCs) under hypoxia
PTEN-induced putative kinase1 (PINK1) and NIX were increased by hypoxia, our results suggest that BNIP3 is a major mitophagy regulator stimulated by hypoxia in UCB-hMSCs, and it has a critical role in regulation of UCB-hMSC functions
Summary
Metabolic alteration of stem cells under hypoxia is prerequisite to controlling stem cell function activated by oxygen signaling [1,2]. The essential metabolic factor that enhances and sustains the functional regulation of stem cells by hypoxia has been incompletely described. There are few studies investigating the role of lipid metabolism altered by hypoxia in stem cell regulation. Despite reactive oxygen species (ROS) accumulation, which causes ischemic injury, the detailed mechanism involved in how stem cells exposed to hypoxia maintain lipid metabolism and function is not fully described. An investigation into factors protecting against impairment of lipid metabolism shift under high ROS accumulation conditions should provide novel insight into the control of stem cells under hypoxia
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