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Mesenchymal stem cells ameliorate hyperglycemia-induced endothelial injury through modulation of mitophagy.

ABSTRACT: Mitochondrial dysfunction and excessive mitochondrial reactive oxygen species (ROS) are fundamental contributors to endothelial injury in diabetic states. Mesenchymal stem cells (MSCs) have exhibited an extraordinary cytoprotective effect that extends to the modulation of mitochondrial homeostasis. However, the underlying mechanisms have not been clearly defined. Emerging evidence has suggested that mitophagy could counteract mitochondrial-derived oxidative stress through the selective elimination of impaired or dysfunctional mitochondria. Therefore, we investigated whether MSCs could ameliorate high-glucose-induced endothelial injury through the modulation of mitophagy. We observed that exposure of human umbilical vein endothelial cells (HUVECs) to high glucose triggers mitochondrial impairment with excessive mitochondrial fragmentation and ROS generation, loss of membrane potential and reduced ATP production. Furthermore, mitophagy was blunted upon high glucose insult, which accelerated dysfunctional mitochondrial accumulation, initiating the mitochondrial apoptotic pathway and, eventually, endothelial dysfunction. MSCs treatment notably attenuated these perturbations accompanied by an enhancement of Pink1 and Parkin expression, whereas these beneficial effects of MSCs were abolished when either Pink1 or Parkin was knocked down. In aortas of diabetic rats, defective mitophagy was observed, which coincided with marked mitochondrial dysfunction. Ultrastructurally, RAECs from diabetic rats revealed a significant reduction in autophagic vacuoles and a marked increase in fragmented mitochondria. Importantly, the infusion of MSCs restored Pink1/Parkin-mediated mitophagy, ameliorated mitochondrial dysfunction and attenuated apoptosis in endothelial cells in diabetic rats. These results suggest that MSCs may protect endothelial cells from hyperglycemia-induced injury by ameliorating mitochondrial dysfunction via Pink1/Parkin -mediated mitophagy.

SUBMITTER: Zhu W

PROVIDER: S-EPMC6078996 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Chronic hyperglycemia causes a progressive decrease of ?-cell function and mass in type 2 diabetic patients. Growing evidence suggests that augment of autophagy may be an effective approach to protect ? cells against various extra-/intracellular stimuli. In this study, we thus investigated whether bone marrow-derived mesenchymal stem cells (BM-MSCs) could ameliorate chronic high glucose (HG)-induced ?-cell injury through modulation of autophagy. Prolonged exposure to HG decreased cell viability, increased cell apoptosis and impaired basal insulin secretion and glucose-stimulated insulin secretion of INS-1 cells, but BM-MSC treatment significantly alleviated these glucotoxic alternations. In addition, western blotting displayed upregulated expression of Beclin1 and LC3-II in INS-1 cells co-cultured with BM-MSCs. Results from immunofluorescence staining and transmission electronic microscope analysis also revealed that BM-MSCs promoted autophagosomes and autolysosomes formation in HG-treated INS-1 cells. However, it should be noted that inhibition of autophagy significantly diminished the protective effects of BM-MSCs on HG-treated INS-1 cells, suggesting that the improvement of ?-cell function and survival induced by BM-MSCs was mediated through autophagy. Furthermore, our results showed that BM-MSCs improved mitochondrial function and reduced reactive oxygen species production in HG-treated INS-1 cells, largely owing to autophagic clearance of impaired mitochondria. In vivo study was performed in rats with type 2 diabetes (T2D). BM-MSC infusion not only ameliorated hyperglycemia, but also promoted restoration of pancreatic ? cells in T2D rats. Meanwhile, BM-MSC infusion upregulated LAMP2 expression and enhanced formation of autophagosomes and autolysosomes, combined with reduced ?-cell apoptosis and increased number of insulin granules. These findings together indicated that BM-MSCs could protect ? cells against chronic HG-induced injury through modulation of autophagy in vitro and in vivo. This study unveiled novel evidence of BM-MSCs as an ideal strategy to enhance autophagy for treatment of T2D mellitus.

Project description:BackgroundHypoxia preconditioning has been proven to be an effective method to enhance the therapeutic action of mesenchymal stem cells (MSCs). However, the beneficial effects of hypoxic MSCs in ischemia/reperfusion (I/R) lung injury have yet to be investigated. In this study, we hypothesized that the administration of hypoxic MSCs would have a positive therapeutic impact on I/R lung injury at molecular, cellular, and functional levels.MethodsI/R lung injury was induced in isolated and perfused rat lungs. Hypoxic MSCs were administered in perfusate at a low (2.5×105 cells) and high (1×106 cells) dose. Rats ventilated with a low tidal volume of 6 ml/kg served as controls. Hemodynamics, lung injury indices, inflammatory responses and activation of apoptotic pathways were determined.ResultsI/R induced permeability pulmonary edema with capillary leakage and increased levels of reactive oxygen species (ROS), pro-inflammatory cytokines, adhesion molecules, cytosolic cytochrome C, and activated MAPK, NF-κB, and apoptotic pathways. The administration of a low dose of hypoxic MSCs effectively attenuated I/R pathologic lung injury score by inhibiting inflammatory responses associated with the generation of ROS and anti-apoptosis effect, however this effect was not observed with a high dose of hypoxic MSCs. Mechanistically, a low dose of hypoxic MSCs down-regulated P38 MAPK and NF-κB signaling but upregulated glutathione, prostaglandin E2, IL-10, mitochondrial cytochrome C and Bcl-2. MSCs infused at a low dose migrated into interstitial and alveolar spaces and bronchial trees, while MSCs infused at a high dose aggregated in the microcirculation and induced pulmonary embolism.ConclusionsHypoxic MSCs can quickly migrate into extravascular lung tissue and adhere to other inflammatory or structure cells and attenuate I/R lung injury through anti-oxidant, anti-inflammatory and anti-apoptotic mechanisms. However, the dose of MSCs needs to be optimized to prevent pulmonary embolism and thrombosis.

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Mesenchymal stem cells ameliorate hyperglycemia-induced endothelial injury through modulation of mitophagy.

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