Jan G. Hengstler and Henryk Zulewski share senior authorship.
Fate of extrahepatic human stem and precursor cells after transplantation into mouse livers†
Article first published online: 1 AUG 2007
Copyright © 2007 American Association for the Study of Liver Diseases
Volume 46, Issue 3, pages 861–870, September 2007
How to Cite
Brulport, M., Schormann, W., Bauer, A., Hermes, M., Elsner, C., Hammersen, F. J., Beerheide, W., Spitkovsky, D., Härtig, W., Nussler, A., Horn, L. C., Edelmann, J., Pelz-Ackermann, O., Petersen, J., Kamprad, M., von Mach, M., Lupp, A., Zulewski, H. and Hengstler, J. G. (2007), Fate of extrahepatic human stem and precursor cells after transplantation into mouse livers. Hepatology, 46: 861–870. doi: 10.1002/hep.21745
Potential conflict of interest: Nothing to report.
- Issue published online: 24 AUG 2007
- Article first published online: 1 AUG 2007
- Manuscript Accepted: 26 MAR 2007
- Manuscript Received: 13 DEC 2006
- Federal Ministry of Education and Research
- HepatoSys. Grant Number: 31P3131
- Interdisciplinary Centre for Clinical Research at the University of Leipzig. Grant Number: 01KS9504, project Z10
In recent years, a large number of groups studied the fate of human stem cells in livers of immunodeficient animals. However, the interpretation of the results is quite controversial. We transplanted 4 different types of human extrahepatic precursor cells (derived from cord blood, monocytes, bone marrow, and pancreas) into livers of nonobese diabetic/severe combined immunodeficiency mice. Human hepatocytes were used as positive controls. Tracking of the transplanted human cells could be achieved by in situ hybridization with alu probes. Cells with alu-positive nuclei stained positive for human albumin and glycogen. Both markers were negative before transplantation. However, cells with alu-positive nuclei did not show a hepatocyte-like morphology and did not express cytochrome P450 3A4, and this suggests that these cells represent a mixed cell type possibly resulting from partial transdifferentiation. Using antibodies specific for human albumin, we also observed a second human albumin–positive cell type that could be clearly distinguished from the previously described cells by its hepatocyte-like morphology. Surprisingly, these cells had a mouse and not a human nucleus which is explained by transdifferentiation of human cells. Although it has not yet been formally proven, we suggest horizontal gene transfer as a likely mechanism, especially because we observed small fragments of human nuclei in mouse cells that originated from deteriorating transplanted cells. Qualitatively similar results were obtained with all 4 human precursor cell types through different routes of administration with and without the induction of liver damage. Conclusion: We observed evidence not for transdifferentiation but instead for a complex situation including partial differentiation and possibly horizontal gene transfer. (HEPATOLOGY 2007.)