Bone marrow mononuclear cell therapy for patients with cirrhosis: a Phase 1 study.

BACKGROUND: Bone marrow-derived cell therapy has been investigated in patients with severe liver disease. AIMS: To assess the feasibility, safety and cell kinetics of autologous bone marrow-derived mononuclear cells (BMMCs) infusion in cirrhotic patients. METHODS: BMMCs were isolated from autologous bone marrow and 10% of the cells were labelled with (99m)Tc-SnCl2. Whole body scintigraphy (WBS) was performed 3 and 24 h after infusion via the hepatic artery. Liver function and image were followed during 1 year. RESULTS: Eight patients received 2.0-15.0 × 108 cells. Three and 24-h WBS showed mean hepatic radiotracer retentions of 41 and 32% respectively. One case of dissection of the hepatic artery and one case of Tako-tsubo syndrome occurred as early complications. A patient developed a cutaneous immunomediated disorder and another patient developed hepatocellular carcinoma (HCC) 12 months after infusion. A reduction in bilirubin was shown at 1 week while serum albumin increased above baseline up to 1 month after infusion (P<0.05). CONCLUSIONS: BMMCs infusion is feasible and practical in a clinical setting. In vivo tracking of labelled cells demonstrated that the hepatic artery route successfully delivered BMMCs to the liver. The early improvement of laboratory indices of liver function should be interpreted with caution, because this study was not designed to evaluate efficacy. The median Model for End-Stage Liver Disease score had not deteriorated 1 year later. The occurrence of a graft-versus-host disease-like phenomenon highlights the importance of sustained vigilance even when giving autologous cells. Controlled studies are needed to determine whether BMMCs infusion affects HCC development in cirrhosis.

Ultrasound imaging in an experimental model of fatty liver disease and cirrhosis in rats.

BACKGROUND: Domestic dogs and cats are very well known to develop chronic hepatic diseases, including hepatic lipidosis and cirrhosis. Ultrasonographic examination is extensively used to detect them. However, there are still few reports on the use of the ultrasound B-mode scan in correlation with histological findings to evaluate diffuse hepatic changes in rodents, which represent the most important animal group used in experimental models of liver diseases. The purpose of this study was to determine the reliability of ultrasound findings in the assessment of fatty liver disease and cirrhosis when compared to histological results in Wistar rats by following up a murine model of chronic hepatic disease. RESULTS: Forty Wistar rats (30 treated, 10 controls) were included. Liver injury was induced by dual exposure to CCl4 and ethanol for 4, 8 and 15 weeks. Liver echogenicity, its correlation to the right renal cortex echogenicity, measurement of portal vein diameter (PVD) and the presence of ascites were evaluated and compared to histological findings of hepatic steatosis and cirrhosis. Liver echogenicity correlated to hepatic steatosis when it was greater or equal to the right renal cortex echogenicity, with a sensitivity of 90%, specificity of 100%, positive and negative predictive values of 100% and 76.9% respectively, and accuracy of 92.5%. Findings of heterogeneous liver echogenicity and irregular surface correlated to liver cirrhosis with a sensitivity of 70.6%, specificity of 100%, positive and negative predictive values of 100% and 82.1% respectively, and accuracy of 87.5%. PVD was significantly increased in both steatotic and cirrhotic rats; however, the later had greater diameters. PVD cut-off point separating steatosis from cirrhosis was 2.1 mm (sensitivity of 100% and specificity of 90.5%). One third of cirrhotic rats presented with ascites. CONCLUSION: The use of ultrasound imaging in the follow-up of murine diffuse liver disease models is feasible and efficient, especially when the studied parameters are used in combination. The potential implication of this study is to provide a non-invasive method that allows follow-up studies of fatty liver disease and cirrhosis of individual rats for pre-clinical drug or cell based therapies.

Bone marrow multipotent mesenchymal stromal cells do not reduce fibrosis or improve function in a rat model of severe chronic liver injury.

The objective of our study was to evaluate the therapeutic potential of bone marrow mesenchymal stromal cells (MSC) in a rat model of severe chronic liver injury. Fourteen female Wistar rats were fed exclusively an alcoholic liquid diet and received intraperitoneal injections of carbon tetrachloride every other day during 15 weeks. After this period, eight animals (MSC group) had 1 x 10(7) cells injected into the portal vein while six animals (placebo group) received vehicle. Blood analysis was performed to evaluate alanine aminotransferase (ALT), aspartate aminotransferase (AST), and albumin before cell therapy and 1 and 2 months after cell or placebo infusion. Fibrosis was evaluated before and 1 month after cell or placebo injection by liver biopsies. Two months after cell delivery, animals were sacrificed and histological analysis of the livers was performed. Fibrosis was quantified by histomorphometry. Biopsies obtained before cell infusion showed intense collagen deposition and septa interconnecting regenerative nodules. One month after cell injection, this result was unaltered and differences in fibrosis quantification were not found between MSC and placebo groups. ALT and AST returned to normal values 2 weeks after cell or placebo infusion, without significant differences between experimental groups. Two months after cell or placebo injection, albumin had also returned to normal values and histological results were maintained, again without differences between MSC and placebo groups. Therefore, under our experimental conditions, MSC were unable to reduce fibrosis or improve liver function in a rat model of severe chronic liver injury.