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The availability of an autologous transplantable auxiliary liver would dramatically affect the treatment of liver disease. Assembly and function in vivo of a bioengineered human liver derived from induced pluripotent stem cells (iPSCs) has not been previously described. By improving methods for liver decellularization, recellularization, and differentiation of different liver cellular lineages of human iPSCs in an organ-like environment, we generated functional engineered human mini livers and performed transplantation in a rat model. Whereas previous studies recellularized liver scaffolds largely with rodent hepatocytes, we repopulated not only the parenchyma with human iPSC-hepatocytes but also the vascular system with human iPS-endothelial cells, and the bile duct network with human iPSC-biliary epithelial cells. The regenerated human iPSC-derived mini liver containing multiple cell types was tested in vivo and remained functional for 4 days after auxiliary liver transplantation in immunocompromised, engineered (IL2rg À/À ) rats.

Background & Aims The cause of hepatic failure in the terminal stages of chronic injury is unknown. Cellular metabolic adaptations in response to the microenvironment have been implicated to cellular breakdown. Methods To address the role of energy metabolism in this process we studied mitochondrial number, respiration, and functional reserve, as well as cellular adenosine-5′-triphosphate (ATP) production, glycolytic flux, and expression of glycolysis related genes in isolated hepatocytes from early and terminal stages of cirrhosis using a model that produces hepatic failure from irreversible cirrhosis in rats. To study the clinical relevance of energy metabolism in terminal stages of chronic liver failure, we analyzed glycolysis and energy metabolism related gene expression in liver tissue from patients at different stages of chronic liver failure according to Child-Pugh classification. Additionally, to determine whether the expression of these genes in early-stage cirrhosis (Child-Pugh Class A) is related to patient outcome, we performed network analysis of publicly available microarray data obtained from biopsies of 216 patients with hepatitis C-related Child-Pugh A cirrhosis who were prospectively followed up for a median of 10 years. Results In the early phase of cirrhosis, mitochondrial function and ATP generation are maintained by increasing energy production from glycolytic flux as production from oxidative phosphorylation falls. At the terminal stage of hepatic injury, mitochondria respiration and ATP production are significantly compromised, as the hepatocytes are unable to sustain the increased demand for high levels of ATP generation from glycolysis. This impairment corresponds to a decrease in glucose-6-phosphatase catalytic subunit and phosphoglucomutase 1. Similar decreased gene expression was observed in liver tissue from patients at different stages of chronic liver injury. Further, unbiased network analysis of microarray data revealed that these genes’ expression was down regulated in the group of patients with poor outcome. Conclusions An adaptive metabolic shift, from generating energy predominantly from oxidative phosphorylation to glycolysis, allows maintenance of energy homeostasis during early stages of liver injury, but leads to hepatocyte dysfunction during terminal stages of chronic liver disease because hepatocytes are unable to sustain high levels of energy production from glycolysis.

Highlights d Edited human iPSCs can control SIRT1 expression d Low SIRT1 expression in human iPSC hepatocytes increases fatty acid biosynthesis d Human iPSC-derived livers developed macrosteatosis and inflammatory phenotype d Metabolic profile in human iPSC-derived fatty livers is similar to human NASH livers

Spontaneous intracholecystic bleeding is very rare. We report herein a very rare case of a pseudoaneurysm of the cystic artery due to acute cholecystitis. A 58-year-old man presented at the emergency department complaining of colicky pain in the right upper quadrant. Dynamic magnetic resonance imaging demonstrated an early-enhanced pooling of contrast material (suggestive of a pseudoaneurysm of the cystic artery) inside the neck of the gallbladder. After the proximal control of the hepatic artery, the patient underwent a cholecystectomy and a ligation of the cystic artery. The resected specimen of the gallbladder showed evidence of a massive intracholecystic hematoma. Proximal to the impacted gallstone in the neck, a 2-cm diameter saccular-type pseudoaneurysm was identified. Although a pseudoaneurysm of the cystic artery is very rare, it should be included in the differential diagnosis of hemobilia. Once the pseudoaneurysm is confirmed, its embolization before a cholecystectomy (which can be attempted laparoscopically) may be useful to ensure the safety of the patient.