Attenuation of Postoperative Acute Liver Failure by Mesenchymal Stem Cell Treatment Due to Metabolic Implications

Objective: To prevent posthepatectomy acute liver failure after extended resection by treatment with mesenchymal stem cells (MSCs). Background: Liver tumors often require extended liver resection, overburdening metabolic and regenerative capacities of the remnant organ. Resulting dysfunction and failure may be improved by the proregenerative characteristics of MSCs. Methods: Extended liver resection was performed in (DPPIV)-deficient F344-Fischer rats. Wild-type animals served as donors of peritoneal adipose-derived MSCs. These were predifferentiated in vitro into hepatocytic cells and delivered to the liver by splenic application. Liver-related blood parameters (international normalized ratio, bilirubin, aspartate aminotransferase, alanine aminotransferase) and liver histology (hematoxylin-eosin, Sudan III) were determined to monitor liver function. Metabolic changes were assessed by metabolomic analyses in the remnant liver and the serum. Liver damage and regeneration were quantified by determination of the apoptotic and proliferation rates. Results: MSCs supported survival after partial hepatectomy. They decreased liver-related blood parameters indicative for the improvement of liver function. The extensive lipid accumulation in hepatocytes illustrating the metabolic overload after resection was attenuated. Treatment with MSCs normalized imbalance of amino acids, acylcarnitines, sphingolipids, and glycerophospholipids in the liver and blood. Furthermore, MSCs decreased the apoptotic rate and increased the proliferation rate. The experimental time period (48 hours) was too short to allow for integration of MSCs into the host liver. Thus, the mode of action was probably indirect. Conclusions: MSCs ameliorated hepatic dysfunction and improved liver regeneration after extended resection by paracrine mechanisms. They may represent a new therapeutic option to treat posthepatectomy acute liver failure.