Hepatocyte transplantation in bile salt export pump‐deficient mice: selective growth advantage of donor hepatocytes under bile acid stress

Journal of Cellular and Molecular Medicine

Huey-Ling Chen¹  Hui-Ling Chen³  Ray-Hwang Yuan²  Shang-Hsin Wu¹  Ya-Hui Chen¹  Chin-Sung Chien¹  Shi-Ping Chou¹  Renxue Wang⁴  Victor Ling⁴ 

[1] Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan;Department of Surgery, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan;Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan;Department of Cancer Genetics, British Columbia Cancer Research Centre, Vancouver, BC, Canada

关键词: cholestasis;    cell therapy;    spgp (sister of p‐glycoprotein);    ATP‐binding cassette transporters;    bile acids;    hepatocyte transplantation;   

DOI  :  10.1111/j.1582-4934.2012.01586.x

来源: Wiley

【 摘 要 】

Abstract

The bile salt export pump (Bsep) mediates the hepatic excretion of bile acids, and its deficiency causes progressive familial intrahepatic cholestasis. The current study aimed to induce bile acid stress in Bsep^−/− mice and to test the efficacy of hepatocyte transplantation in this disease model. We fed Bsep^−/− and wild-type mice cholic acid (CA) or ursodeoxycholic acid (UDCA). Both CA and UDCA caused cholestasis and apoptosis in the Bsep^−/− mouse liver. Wild-type mice had minimal liver injury and apoptosis when fed CA or UDCA, yet had increased proliferative activity. On the basis of the differential cytotoxicity of bile acids on the livers of wild-type and Bsep^−/− mice, we transplanted wild-type hepatocytes into the liver of Bsep^−/− mice fed CA or CA + UDCA. After 1–6 weeks, the donor cell repopulation and canalicular Bsep distribution were documented. An improved repopulation efficiency in the CA + UDCA-supplemented group was found at 2 weeks (4.76 ± 5.93% vs. 1.32 ± 1.48%, P = 0.0026) and at 4–6 weeks (12.09 ± 14.67% vs. 1.55 ± 1.28%, P < 0.001) compared with the CA-supplemented group. Normal-appearing hepatocytes with prominent nuclear staining for FXR were noted in the repopulated donor nodules. After hepatocyte transplantation, biliary total bile acids increased from 24% to 82% of the wild-type levels, among which trihydroxylated bile acids increased from 41% to 79% in the Bsep^−/− mice. We conclude that bile acid stress triggers differential injury responses in the Bsep^−/− and wild-type hepatocytes. This strategy changed the balance of the donor–recipient growth capacities and was critical for successful donor repopulation.

【 授权许可】

Unknown   
© 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd