Functional integration of human mesenchymal stem cell-derived hepatocytes into mouse livers

Ines Aurich ^1*, Lutz P. Mueller ², Hendryk Aurich ¹, Jana Luetzkendorf ², Kai Tisljar ¹, Matthias Dollinger ¹, Wiebke Schormann ³, Jens Walldorf ¹, Jan Hengstler ³, Wolfgang E. Fleig ¹ and Bruno Christ ¹

¹ 1st Department of Medicine, Martin Luther University Halle-Wittenberg, Germany
² 4th Department of Medicine, Martin Luther University Halle-Wittenberg, Germany
³ Dept. of Molecular and Forensic Toxicology, University of Leipzig, Germany

^* To whom correspondence should be addressed. E-mail: ines.aurich{at}medizin.uni-halle.de.

Accepted 15 August 2006

Abstract

Aims: At present, clinical success of hepatocyte transplantation as an alternative to whole liver transplantation is hampered by the limited availability of suitable donor organs for the isolation of transplantable hepatocytes. Hence, novel cell sources are required to deliver hepatocytes of adequate quality for clinical use. Mesenchymal stem cells (MSC) from human bone marrow may have the potential to differentiate into hepatocytes in vitro and in vivo.

Methods: Isolated MSC were selected by density gradient centrifugation and plastic adherence, differentiated in the presence of human hepatocyte growth medium and transplanted in immunodeficient Pfp/Rag2 mice.

Results: Here, we demonstrate that human MSC gain in vitro the characteristic morphology and function of hepatocytes in response to specified growth factors. Specifically pre-conditioned MSC store glycogen, synthesise urea and feature the active hepatocyte- specific gene promotor of phosphoenolpyruvate carboxykinase (PCK1). After transplantation into livers of immunodeficient mice, pre-conditioned MSC engraft predominantly in the periportal portion of the liver lobule. In situ, the cells continue to store glycogen and express PCK1, connexin32, albumin and the human hepatocyte-specific antigen HepPar1, indicating that the transplanted cells retain prominent qualities of hepatocytes after their regional integration.

Conclusion: Thus, human bone marrow-derived MSC may serve as a novel source for the propagation of hepatocyte-like cells suitable for cell therapy in liver diseases.

Keywords: cell transplantation, hepatogenic differentiation, human mesenchymal stem cells

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Relevant Article

Digest

Emad El-Omar
Gut 2007 56: 313. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

• Aurich, H, Sgodda, M, Kaltwasser, P, Vetter, M, Weise, A, Liehr, T, Brulport, M, Hengstler, J G, Dollinger, M M, Fleig, W E, Christ, B (2009). Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo. Gut 58: 570-581 [Abstract] [Full Text]  
• Brezillon, N., Kremsdorf, D., Weiss, M. C. (2008). Cell therapy for the diseased liver: from stem cell biology to novel models for hepatotropic human pathogens. DMM 1: 113-130 [Abstract] [Full Text]  
• Weiss, T S, Lichtenauer, M, Kirchner, S, Stock, P, Aurich, H, Christ, B, Brockhoff, G, Kunz-Schughart, L A, Jauch, K-W, Schlitt, H-J, Thasler, W E (2008). Hepatic progenitor cells from adult human livers for cell transplantation. Gut 57: 1129-1138 [Abstract] [Full Text]  
• Sato, Y., Yamada, H., Iwasaki, K., Tateno, C., Yokoi, T., Yoshizato, K., Horii, I. (2008). Human Hepatocytes Can Repopulate Mouse Liver: Histopathology of the Liver in Human Hepatocyte-Transplanted Chimeric Mice and Toxicologic Responses to Acetaminophen. Toxicol Pathol 36: 581-591 [Abstract] [Full Text]  
• di Bonzo, L V., Ferrero, I, Cravanzola, C, Mareschi, K, Rustichell, D, Novo, E, Sanavio, F, Cannito, S, Zamara, E, Bertero, M, Davit, A, Francica, S, Novelli, F, Colombatto, S, Fagioli, F, Parola, M (2008). Human mesenchymal stem cells as a two-edged sword in hepatic regenerative medicine: engraftment and hepatocyte differentiation versus profibrogenic potential. Gut 57: 223-231 [Abstract] [Full Text]