Bone marrow derived-mesenchymal stem cell improves diabetes-associated fatty liver via mitochondria transformation in mice

Abstract

Background Non-alcoholic fatty liver disease (NAFLD) has become a global epidemic disease. Its incidence is associated with type 2 diabetes mellitus (T2DM). Presently, there is no approved pharmacological agents specially developed for NAFLD. One promising disease-modifying strategy is the transplantation of stem cells to promote metabolic regulation and repair of injury. Method In this study, a T2DM model was established through 28-week high-fat diet (HFD) feeding resulting in T2DM-associated NAFLD, followed by the injection of bone marrow mesenchymal stem cells (BMSCs). The morphology, function, and transfer of hepatocyte mitochondria were evaluated in both vivo and in vitro. Results BMSC implantation resulted in the considerable recovery of increasing weight, HFD-induced steatosis, liver function, and disordered glucose and lipid metabolism. The treatment with BMSC transplantation was accompanied by reduced fat accumulation. Moreover, mitochondrial transfer was observed in both vivo and vitro studies. And the mitochondria-recipient steatotic cells exhibited significantly enhanced OXPHOS activity, ATP production, and mitochondrial membrane potential, and reduced reactive oxygen species levels, which were not achieved by the blocking of mitochondrial transfer. Conclusion Mitochondrial transfer from BMSCs is a feasible process to combat NAFLD via rescuing dysfunction mitochondria, and has a promising therapeutic effect on metabolism-related diseases.

Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH)

“…In other novel studies with cell therapy implication, bone marrow-derived MSCs (BMSCs) were shown to regulate mitochondrial quality control, improve mitochondrial dysfunction, lower the AST/ALT ratio and alleviate the steatosis and histological lesions in livers of diabetic NAFL mice via mitochondrial transfer between stem cells and steatosis hepatocytes. 540 BMSCs engrafted within the liver tissue prevented histological alterations and collagen accumulation via upregulating hepatic Nrf2/HO-1 signaling pathway in CCl 4 -intoxicated rats. 543 In addition, BM-MSCs also attenuated hepatic fibrosis by secreting IL-4 and IL-10 to promote macrophage phenotypic switch from profibrotic Ly6C hi subset to restorative Ly6C lo subpopulation, which significantly blocked the source of fibrogenic cytokines (TGF-β, PDGF, TNF-α, and IL-1β) from Ly6C hi macrophages.…”

“…The therapeutic efficacy of MSCs mainly relies on the paracrine actions on different cell type, differentiation of MSCs, and inflammatory actions in the liver. 540 In the preclinical studies, hUC-MSCs transplantation improves liver function, the degree of fibrosis, and promotes liver repair in acute-on-chronic liver failure/acute-on-chronic liver injury rats by inhibiting Notch signaling and reversing the imbalance of the Stat1/Stat3 pathway. 541 Contrarily, adipose-derived stem cells (ADSCs) treatment reduces apoptosis of hepatocytes through Notch signaling activation and contributes to the repair and regeneration of the liver in NASH mouse model.…”

Systemic proteomics and miRNA profile analysis of exosomes derived from human pluripotent stem cells

“…However, their direct application in treatment is limited due to the risk of malignancy and ethical issues [ 31 ]. In contrast, mesenchymal stem cells (MSCs) have a broader application for intervention in multiple diseases in clinical settings [ 8 ]. However, their direct use still faces several limitations, including a low survival rate, immunological rejection, and safety issues [ 8 , 43 ].…”

“…In contrast, mesenchymal stem cells (MSCs) have a broader application for intervention in multiple diseases in clinical settings [ 8 ]. However, their direct use still faces several limitations, including a low survival rate, immunological rejection, and safety issues [ 8 , 43 ]. Currently, much attention has been paid to exosomes because of their biosecurity, stability, non-aneuploidy, and low immunogenicity [ 51 ].…”

Mitochondrial transplantation: opportunities and challenges in the treatment of obesity, diabetes, and nonalcoholic fatty liver disease

“…Similarly, in an HFD-induced NAFLD model, mitochondrial transfer from BMSCs to steatotic cells was observed to reduce fat accumulation. The recipient steatotic cells markedly enhanced liver function, OXPHOS activity, ATP production, and Δψ mt while reducing ROS levels, weight gain, steatosis, and disturbances in glucose and lipid metabolism in obese mice [ 120 ]. In contrast, umbilical cord MSCs have been shown to have clinical promise due to their accessibility, expandability, and multipotentiality.…”