RETRACTED ARTICLE: Mesenchymal stem cell-derived exosomes exert ameliorative effects in type 2 diabetes by improving hepatic glucose and lipid metabolism via enhancing autophagy

Abstract

Background: Mesenchymal stem cell (MSC)-based therapy is currently considered to be an effective treatment strategy for diabetes and hepatic disorders, such as liver cirrhosis and non-alcoholic fatty liver disease. Exosomes are important mediators of cellular connections, and increasing evidence has suggested that exosomes derived from MSCs may be used as direct therapeutic agents; their mechanisms of action, however, remain largely unclear. Here, we evaluated the efficacy and molecular mechanisms of human umbilical cord MSC-derived exosomes (HucMDEs) on hepatic glucose and lipid metabolism in type 2 diabetes mellitus (T2DM). Methods: HucMDEs were used to treat T2DM rats, as well as palmitic acid (PA)-treated L-O2 cells, in order to determine the effects of HucMDEs on hepatic glucose and lipid metabolism. To evaluate the changes in autophagy and potential signaling pathways, autophagy-related proteins (BECN1, microtubule-associated protein 1 light chain 3 beta [MAP 1LC3B]), autophagy-related genes (ATGs, ATG5, and ATG7), AMP-activated protein kinase (AMPK), and phosphorylated AMPK (p-AMPK) were assessed by Western blotting. Results: HucMDEs promoted hepatic glycolysis, glycogen storage, and lipolysis, and reduced gluconeogenesis. Additionally, autophagy potentially contributed to the effects of HucMDE treatment. Transmission electron microscopy revealed an increased formation of autophagosomes in HucMDE-treated groups, and the autophagy marker proteins, BECN1 and MAP 1LC3B, were also increased. Moreover, autophagy inhibitor 3-methyladenine significantly reduced the effects of HucMDEs on glucose and lipid metabolism in T2DM rats. Based on its phosphorylation status, we found that the AMPK signaling pathway was activated and induced autophagy in T2DM rats and PA-treated L-O2 cells. Meanwhile, the transfection of AMPK siRNA or application of the AMPK inhibitor, Comp C, weakened the therapeutic effects of HucMDEs on glucose and lipid metabolism.

Programmed cell death in stem cell-based therapy: Mechanisms and clinical applications

“…As a self-protective catabolic mechanism within the cells, autophagy exerts a key influence in sustaining SC homeostasis by maintaining stemness, upregulating quiescence, managing differentiation via remodeling, and self-renewal via metabolic reprogramming[ 170 - 173 ]. Autophagy contributes to metabolic regulation through increased glycolysis to generate ATP in the hypoxic milieu for balancing SC fate[ 174 , 175 ]. For example, autophagy plays a vital role in maintaining the quiescence of SCs ( e.g.…”

Adipose Extracellular Vesicles: Messengers From and to Macrophages in Regulating Immunometabolic Homeostasis or Disorders

“…Subsequently, several other studies confirmed that exosomes from either human or mouse ADSCs showed similar effects on macrophages, and more importantly, these exosomes were applied into the treatment of different disease models related inflammation or injury in animals (73,(126)(127)(128)(129)(130). Notably, the therapeutic potentials of ADSC-derived EVs have also been reported in metabolism-related disease models such as type 1, type 2 diabetes or diabetic nephropathy, and more target cells like T cells, hepatocytes or podocytes have been revealed (131)(132)(133)(134)(135). All these observations suggest that ADSC-derived EVs may regulate immunometabolic homeostasis in multiple ways.…”

A Comprehensive Review on Factors Influences Biogenesis, Functions, Therapeutic and Clinical Implications of Exosomes

“…These findings suggest that HucMDEs improve hepatic glucose and lipid metabolism in T2DM rats by activating autophagy via the AMPK pathway. 207 Liver fibrosis is a serious disorder caused by prolonged parenchymal cell death, leading to the activation of fibrogenic cells, extracellular matrix accumulation, and eventually liver fibrosis. Exosomes derived from adipose-derived mesenchymal stem cells (ADSCs) have been used to deliver circular RNAs mmu_circ_0000623 to treat liver fibrosis.…”