Mesenchymal stromal cells protect hepatocytes from lipotoxicity through alleviation of endoplasmic reticulum stress by restoring SERCA activity

Li, Linzhao; Zeng, Xin; Liu, Zhenzhen; Chen, Xuanming; Li, Lan; Luo, Ruixi; Liu, Xiaohong; Zhang, Jie; Liu, Jingping; Liu, Yanrong; Cheng, Jun; Chen, Younan

doi:10.1111/jcmm.16338

Cited by 30 publications

(27 citation statements)

References 41 publications

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“…In high fat diet (HFD)-induced rats with NAFLD, rat BM-MSC transplantation alleviated ATF4 and CHOP expression [32]. Additionally, MSC treatment in palmitic acid-induced hepatocytes reduced CHOP expression, whereas SERCA2b silencing reversed the ER stress response and calcium homeostasis [33]. These data are similar to our data showing that CHOP expression and PERK-eIF2α-ATF4 signaling were increased in the BDL-injured rat model (Fig.…”

Section: Discussionsupporting

confidence: 88%

Activation of the EGFR-PI3K-CaM Pathway by PRL-1 Ameliorates Liver Cirrhosis via ER Stress-dependent Calcium

Kim¹,

Kim²,

Park³

et al. 2021

Preprint

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Background: Accumulation of cholesterol and depletion of calcium induce hepatic injury through the endoplasmic reticulum (ER) stress response. ER stress regulates the calcium imbalance between the ER and mitochondria. Previously, we reported that phosphatase of regenerating liver-1 (PRL-1)-overexpressing placenta-derived mesenchymal stem cells (PD-MSCsPRL-1) promoted liver regeneration through mitochondrial dynamics in a cirrhotic rat model. However, whether PRL-1 is involved in ER stress-dependent calcium is unclear. So, we demonstrated that PD-MSCsPRL-1 improves hepatic functions by regulating ER stress and calcium channels in a rat model of bile duct ligation (BDL). Methods: Liver cirrhosis was induced in Sprague-Dawley (SD) rats using surgically induced BDL for 10 days. PD-MSCs and PD-MSCsPRL-1 (2x106 cells) were intravenously administered to animals, and their therapeutic effects were analyzed. WB-F344 cells exposed to thapsigargin (TG) were cocultured with PD-MSCs or PD-MSCsPRL-1. Results: ER stress markers (e.g., eIF2α, ATF4, and CHOP) were increased in the non-transplantation group (NTx) compared with the control group. PD-MSCsPRL-1 significantly decreased ER stress markers compared to NTx and induced dynamic changes in calcium channel markers (e.g., SERCA2b, IP3R, MCU, and VDAC1) (*p<0.05). In TG-treated WB-F344 cells, cocultivation with PD-MSCsPRL-1 decreased cytosolic CaM expression and cytosolic and mitochondrial Ca2+ concentrations; however, the ER Ca2+ concentration was increased compared to that in PD-MSCs (*p<0.05). Additionally, PRL-1 through epidermal growth factor receptor (EGFR) activated phosphatidylinositol-3-kinase (PI3K) signaling, resulting in calcium increases via CaM expression. Conclusions: These findings suggest that PD-MSCsPRL-1 improved hepatic functions through calcium changes and attenuated ER stress in a BDL-injured rat model. Therefore, these results provide useful data for the development of next-generation MSC-based stem cell therapy for regenerative medicine in chronic liver disease.

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Section: Discussionsupporting

confidence: 88%

Activation of the EGFR-PI3K-CaM Pathway by PRL-1 Ameliorates Liver Cirrhosis via ER Stress-dependent Calcium

Kim¹,

Kim²,

Park³

et al. 2021

Preprint

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“…However, there are no reports on evaluating the treatment effect of BMSCs on NAFLD in T2DM. To date, only two studies have detailed the therapeutic effect of BMSCs on the HFD-induced rodent NAFLD model [ 50 , 51 ]. However, neither has described the role of BMSCs in T2DM-associated NAFLD.…”

Section: Discussionmentioning

confidence: 99%

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

Guo²,

Zhang

et al. 2021

Stem Cell Res Ther

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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.

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“…Mechanistically, however, the mode of MSC action remains largely elusive. Recent reports identified lipotoxicity and ER stress as MSC targets, which were inhibited by MSC treatment of rats suffering from high-fat-diet-induced NASH [ 25 ]. In a mouse model of NASH-associated diabetes, an MSC-conditioned medium improved both NASH and insulin sensitivity by targeting mitochondria [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Human Mesenchymal Stromal Cells Resolve Lipid Load in High Fat Diet-Induced Non-Alcoholic Steatohepatitis in Mice by Mitochondria Donation

Nickel

Christ

Schmidt

et al. 2022

Cells

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Mesenchymal stromal cells (MSC) increasingly emerge as an option to ameliorate non-alcoholic steatohepatitis (NASH), a serious disease, which untreated may progress to liver cirrhosis and cancer. Before clinical translation, the mode of action of MSC needs to be established. Here, we established NASH in an immune-deficient mouse model by feeding a high fat diet. Human bone-marrow-derived MSC were delivered to the liver via intrasplenic transplantation. As verified by biochemical and image analyses, human mesenchymal stromal cells improved high-fat-diet-induced NASH in the mouse liver by decreasing hepatic lipid content and inflammation, as well as by restoring tissue homeostasis. MSC-mediated changes in gene expression indicated the switch from lipid storage to lipid utilization. It was obvious that host mouse hepatocytes harbored human mitochondria. Thus, it is feasible that resolution of NASH in mouse livers involved the donation of human mitochondria to the mouse hepatocytes. Therefore, human MSC might provide oxidative capacity for lipid breakdown followed by restoration of metabolic and tissue homeostasis.

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Mesenchymal stromal cells protect hepatocytes from lipotoxicity through alleviation of endoplasmic reticulum stress by restoring SERCA activity

Cited by 30 publications

References 41 publications

Activation of the EGFR-PI3K-CaM Pathway by PRL-1 Ameliorates Liver Cirrhosis via ER Stress-dependent Calcium

Activation of the EGFR-PI3K-CaM Pathway by PRL-1 Ameliorates Liver Cirrhosis via ER Stress-dependent Calcium

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

Human Mesenchymal Stromal Cells Resolve Lipid Load in High Fat Diet-Induced Non-Alcoholic Steatohepatitis in Mice by Mitochondria Donation

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