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Ischemia-reperfusion (IR) is an inevitable complication of liver surgery. Recent studies indicate a critical role of endoplasmic reticulum stress (ERS) in hepatic IR. Mesenchymal stem cells (MSCs) have proven to be an effective tool for tissue regeneration and treatment of various diseases, including that of the liver. However, the mechanisms underlying the therapeutic effects of stem cells on hepatic IR injury (IRI) are still poorly understood, especially in the context of ERS. In this study, we established a porcine model of hepatic IRI and partial hepatectomy, and transplanted the animals with adipose-derived mesenchymal stem cells (ADSCs) isolated from miniature pigs. ADSCs not only alleviated the pathological changes in the liver parenchyma following IRI, but also protected the resident hepatocytes from damage. Mechanistically, the ADSCs significantly downregulated ERS-related proteins, including GRP78, p-eIF2α, ATF6 and XBP1s, as well as the proteins involved in ERS-induced apoptosis like p-JNK, ATF4 and CHOP. Taken together, ADSCs can alleviate hepatic IRI by inhibiting ERS and its downstream apoptotic pathways in the hepatocytes, indicating its therapeutic potential in liver diseases.

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Hepatic ischemia-reperfusion (I/R) injury is inevitable during hepatectomy and may cause both postoperative morbidity and mortality. Regenerative medicine suggested adipose-derived stem cells (ADSCs) as an attractive tool for the treatment of liver diseases. In this study, we investigated the effect of ADSCs in an I/R model combined with laparoscopic hepatectomy in swine. Eighteen Bama miniature pigs were randomly divided into Sham, IRI, and ADSCs groups. ADSCs (1 × 106/kg) were injected through liver parenchyma immediately after hemihepatectomy. The apoptosis-related role of ADSCs was studied. The results showed that ADSCs transplantation reduced both pathological and ultrastructural changes and decreased the number of apoptotic-positive cells. In the ADSCs group, Fas, Fas ligand (FasL) protein, and mRNA were downregulated and the enzyme activities of Caspase3, Caspase8, and Caspase9 were significantly decreased. In addition, ADSC therapy significantly increased the ratio of Bcl-2/Bax protein and mRNA compared to the IRI group. In conclusion, ADSCs attenuated both I/R and hepatectomy-induced liver apoptosis in a porcine model, and offers a potential therapeutic option for hepatic I/R and hepatectomy.

Aim To study the anti-inflammatory and liver regenerative effects of adipose-derived mesenchymal stem cells (ADSCs) on a porcine model of ischemia-reperfusion (IR) and hemihepatectomy. Methods Eighteen healthy Bama miniature pigs were randomly divided into the sham-operated (sham), untreated IR injury (IRI), and ADSC-transplanted (ADSC) groups. Hepatic IR was established by laparoscopic hemihepatectomy. ADSCs were transplanted directly into the liver parenchyma after the surgery. Hepatic inflammation and liver regeneration were evaluated by histopathological examination and assessment of relevant cytokines and other factors. Results ADSC transplantation successfully ameliorated the IRI-induced histopathological damage and the high levels of pro-inflammatory cytokines like IL-1β, IL-6, and TNF-α. In addition, the ADSCs enhanced the expression of the anti-inflammatory IL-10, regenerative factors including HGF, Cyclin D1, and proliferating cell nuclear antigen (PCNA), and angiogenic factors like VEGF, ANG-1, and ANG-2. Conclusions ADSCs attenuated the hepatic IRI-induced inflammatory response and promoted liver regeneration.