Bone marrow engraftment in a rodent model of chemical carcinogenesis but no role in the histogenesis of hepatocellular carcinoma

• Published in: Gut 2004-06, Vol.53 (6), p.884-889
• Main Authors: Ishikawa, H, Nakao, K, Matsumoto, K, Nishimura, D, Ichikawa, T, Hamasaki, K, Eguchi, K
• Format: Article
• Language: English
• Subjects: AFP; animal study; Animals; beta-Galactosidase - metabolism; Biological and medical sciences; BMT; Bone marrow; bone marrow cell; Bone Marrow Transplantation; Carcinoma, Hepatocellular - chemically induced; Cell Transformation, Neoplastic - chemically induced; diethylnitrosamine/phenobarbital; Female; FISH; fluorescence in situ hybridisation; Galactosides; Gastroenterology. Liver. Pancreas. Abdomen; Graft Survival; H&E; haematoxylin-eosin; HCC; Hepatitis; hepatocarcinogenesis; hepatocellular carcinoma; Hepatocytes - pathology; Immunohistochemistry; Indoles; Liver; Liver cancer; Liver Neoplasms, Experimental - chemically induced; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Mice; Mice, Transgenic; NDEA/PB; stem cell; Stem cells; Stem Cells - metabolism; Stem Cells - pathology; Studies; Survival Rate; Tumors; α-fetoprotein; β-gal; β-galactosidase
• ISSN: 0017-5749; 1468-3288; 1458-3288
• DOI: 10.1136/gut.2003.026047

Background and aim: Recent studies indicated that hepatic stem cells in the bone marrow could differentiate into mature hepatocytes, suggesting that bone marrow cells could be used for replacement of damaged hepatocytes in a variety of liver diseases. Hepatocellular carcinoma (HCC) is thought to arise from hepatic stem cells. In this study, we investigated the malignant potential of hepatic stem cells derived from the bone marrow in a mouse model of chemical hepatocarcinogenesis. Methods: Bone marrow cells were obtained from the male β-galactosidase (β-gal) transgenic mouse and transplanted into female recipient mice. Hepatocarcinogenesis was induced by a year of treatment with diethylnitrosamine and phenobarbital (NDEA/PB). One year later, the liver was removed from each treated mouse and evaluated by x-gal staining, immunohistochemistry, and fluorescence in situ hybridisation (FISH). Results: Forty per cent of recipient mice survived and developed multiple HCC. Clusters of β-gal positive mature hepatocytes were detected sporadically in the entire liver of NDEA/PB treated mice who underwent bone marrow transplantation (BMT) with while no such hepatocytes were identified in the liver of BMT mice that were not treated with NDEA/PB. The Y chromosome was detected with the same frequency as the donor male liver in clusters of β-gal positive mature hepatocytes by FISH. However, no HCC was positive for β-gal or the Y chromosome. Immunohistochemically, β-gal positive mature hepatocytes did not express CD34 or α-fetoprotein. Conclusions: Our results suggest that hepatic stem cells derived from the bone marrow have low malignant potential, at least in our model.