Abstract
Chronic hyperglycemia causes a progressive decrease of β-cell function and mass in type 2 diabetic patients. Growing evidence suggests that augment of autophagy may be an effective approach to protect β 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 β-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 β-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 β cells in T2D rats. Meanwhile, BM-MSC infusion upregulated LAMP2 expression and enhanced formation of autophagosomes and autolysosomes, combined with reduced β-cell apoptosis and increased number of insulin granules. These findings together indicated that BM-MSCs could protect β 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.
Highlights
Mesenchymal stem cells (MSCs), one class of pluripotent cells that are capable of differentiating into multi-lineage cells,[6] counteracting autoimmunity[7] and secreting various cytokines and growth factors,[8] have exhibited significant anti-diabetic effects in animal studies and clinical trials.[9,10,11] Research conducted by Liu et al.[12] indicated that, treatment with Wharton’s Jelly-derived MSCs improved metabolic control and β-cell function in patients with Type 2 diabetes (T2D) mellitus
We measured cell viability using cell counting kit-8 (CCK-8) assay, and the results showed that chronic exposure of INS-1 cells to high glucose (HG) decreased cell viability compared with untreated control cells, but bone marrow (BM)-MSC treatment significantly improved this alternation (Figure 1a)
BM-MSC co-culture significantly downregulated the expression of cleaved caspase 3 and reduced the apoptotic incidence, indicating that BM-MSCs could inhibit INS-1 cell apoptosis induced by chronic HG (Figures 1b–e)
Summary
Mesenchymal stem cells (MSCs), one class of pluripotent cells that are capable of differentiating into multi-lineage cells,[6] counteracting autoimmunity[7] and secreting various cytokines and growth factors,[8] have exhibited significant anti-diabetic effects in animal studies and clinical trials.[9,10,11] Research conducted by Liu et al.[12] indicated that, treatment with Wharton’s Jelly-derived MSCs improved metabolic control and β-cell function in patients with T2D mellitus. Recent research indicated that MSCs stimulated autophagy and cleared accumulated toxic proteins, contributing to increased neuronal survival in neurodegenerative disorders.[27,28] there is currently no evidence describing the potential impacts of MSCs on autophagy in the dysfunctional β cells of T2D. Mitochondria have an imperative role in glucose-stimulated insulin secretion (GSIS) and β-cell survival.[29,30] During chronic hyperglycemia, impaired mitochondria leads to considerable production of reactive oxygen species (ROS), which in turn aggravates mitochondrial damage and other intracellular abnormalities, contributing to β-cell dysfunction and apoptosis.[31] several studies have reported that autophagy can remove damaged organelles, such as mitochondria, as an adaptive response to unfavorable circumstances. Our results showed that BM-MSCs enhanced autophagy and thereby protect β cells against chronic HG-induced injury in vitro, and in vivo, the autophagic activity of pancreatic β cells could be modulated by BM-MSC infusion in T2D rats. This study may provide novel and important evidence supporting future clinical use of MSC therapy for T2D
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