These authors contributed equally to this work.
Ectopic expression of murine CD47 minimizes macrophage rejection of human hepatocyte xenografts in immunodeficient mice†
Article first published online: 4 OCT 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 4, pages 1479–1488, October 2012
How to Cite
Waern, J. M., Yuan, Q., Rüdrich, U., Becker, P. D., Schulze, K., Strick-Marchand, H., Huntington, N. D., Zacher, B. J., Wursthorn, K., DiSanto, J. P., Guzman, C. A., Manns, M. P., Ott, M. and Bock, M. (2012), Ectopic expression of murine CD47 minimizes macrophage rejection of human hepatocyte xenografts in immunodeficient mice. Hepatology, 56: 1479–1488. doi: 10.1002/hep.25816
Potential conflict of interest: Nothing to report.
- Issue published online: 4 OCT 2012
- Article first published online: 4 OCT 2012
- Accepted manuscript online: 26 APR 2012 05:43AM EST
- Manuscript Accepted: 20 APR 2012
- Manuscript Received: 7 DEC 2011
- START-MSC2 program of the BMBF
- M.O. supporting J.M.W.
- GCGH-program GC4 (Bill and Melinda Gates Foundation) to J.D.S., C.A.G., M.P.M., and M.O.
- REBIRTH Cluster of Excellence (Deutsche Forschungsgemeinschaft) to U.R., C.A.G., M.P.M., M.O., and M.B. Q.Y.
- SFB 738 (Deutsche Forschungsgemeinschaft) awarded to M.O.
Macrophages play an important role in the rejection of xenogeneic cells and therefore represent a major obstacle to generating chimeric mice with human xenografts that are useful tools for basic and preclinical medical research. The signal inhibitory regulatory protein α (SIRPα) receptor is a negative regulator of macrophage phagocytic activity and interacts in a species-specific fashion with its ligand CD47. Furthermore, SIRPα polymorphism in laboratory mouse strains significantly affects the extent of human CD47-mediated toleration of human xenotransplants. Aiming to minimize macrophage activity and thus optimize human cell engraftment in immunodeficient mice, we lentivirally transduced murine CD47 (Cd47) into human liver cells. Human HepG2 liver cells expressing Cd47 were less frequently contacted and phagocytosed by murine RAW264.7 macrophages in vitro than their Cd47-negative counterparts. For the generation of human-mouse chimeric livers in immunodeficient BALB-ΔRAG/γc-uPA (urokinase-type plasminogen activator) mice, freshly thawed cryopreserved human hepatocytes were transduced with a lentiviral expression vector for Cd47 using a refined in vitro transduction protocol immediately before transplantation. In vivo, Cd47-positive human primary hepatocytes were selectively retained following engraftment in immunodeficient mice, leading to at least a doubling of liver repopulation efficiencies. Conclusion: We conclude that ectopic expression of murine Cd47 in human hepatocytes selectively favors engraftment upon transplantation into mice, a finding that should have a profound impact on the generation of robust humanized small animal models. Moreover, dominance of ectopically expressed murine Cd47 over endogenous human CD47 should also widen the spectrum of immunodeficient mouse strains suitable for humanization. (HEPATOLOGY 2012)