Carcinogenesis Advance Access originally published online on January 3, 2008
Carcinogenesis 2008 29(2):448-454; doi:10.1093/carcin/bgm279
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Bone marrow-derived cells fuse with hepatic oval cells but are not involved in hepatic tumorigenesis in the choline-deficient ethionine-supplemented diet rat model
Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
1 Department of Organ Regeneration, Institute of Organ Transplants, Reconstructive Medicine and Tissue Engineering, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
* To whom correspondence should be addressed. Tel: +81 263 37 2654; Fax: +81 263 35 1282; Email: jsoeda{at}hsp.md.shinshu-u.ac.jp
Bone marrow cells (BMCs) have been reported to behave as tissue-specific stem cells in some organs and to participate in tumorigenesis. However, the roles of BMCs in hepatic regeneration and carcinogenesis are still unknown. A choline-deficient, ethionine-supplemented (CDE) diet leads to the appearance of oval cells, a type of hepatic progenitor cell, and activates their replication. Furthermore, this type of diet induces preneoplastic nodules and hepatocellular carcinomas (HCCs) derived from oval cell progenitors. The aims of this study were to determine whether oval cells are derived from BMCs and whether preneoplastic nodules or HCCs originate from BMCs in the CDE diet rat model. To clarify the origin of constituent cells in the liver, we transplanted BMCs from green fluorescent protein (GFP) transgenic female rats into male Lewis rats, which were then exposed to a CDE diet to induce hepatocarcinogenesis. Some oval cells showed both donor-derived GFP expression and the recipient-specific Y chromosome, indicating that donor BMCs fused with recipient oval cells. Several preneoplastic nodules (precancerous lesions) identified by their glutathione S-transferase placental (GSTp) positivity were induced by CDE treatment. However, these preneoplastic GSTp-positive nodules were not GFP positive. In conclusion, this study has produced two major findings. First, BMCs fuse with some oval cells. Second, BMC-fused oval cells and BMCs might not have malignant potential in the CDE-treated rat model.
Abbreviations: 2-AAF, 2-acetylaminofluorene; BMC, bone marrow cell; BMT, bone marrow transplantation; CDE, choline-deficient, ethionine-supplemented; CK, cytokeratin; DEN, diethylnitrosamine; GFP, green fluorescent protein; GSTp, glutathione S-transferase placental; HCC, hepatocellular carcinoma; PBS, phosphate-buffered saline
Received July 13, 2007; revised November 7, 2007; accepted December 1, 2007.