HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 2005-0405v1 24/4/1104    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kashofer, K. Articles by Bonnet, D. Search for Related Content PubMed PubMed Citation Articles by Kashofer, K. Articles by Bonnet, D.

TISSUE-SPECIFIC STEM CELLS

In Vivo Formation of Unstable Heterokaryons after Liver Damage and Hematopoietic Stem Cell/Progenitor Transplantation

Hematopoietic Stem Cell Laboratory, Cancer Research UK, London Research Institute, London, United Kingdom

Key Words. Fusion • Hepatocytes • Hematopoietic stem cells • Plasticity

Correspondence: Dominique Bonnet, Ph.D., Hematopoietic Stem Cell Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln’s Inn Fields, London, WC2A 3PX, United Kingdom. Telephone: 020 72693281; Fax: 020 72693581; e-mail: d.bonnet{at}cancer.org.uk

Received on August 22, 2005; accepted for publication on November 2, 2005.

Following reports of lineage plasticity in human hematopoietic stem cells (HSCs), we investigated the potential of human cord blood HSC-enriched cells to create hepatocytes in hosts after inducing liver damage. Carbon tetrachloride induces severe liver damage and subsequent repair via mitosis of resident hepatocytes. It additionally leads to a threefold increase in homing of human mononuclear cells to bone marrow and liver and subsequently to a substantial enhancement of bone marrow engraftment. Eight weeks after liver damage and infusion of an enhanced green fluorescent protein (eGFP) lentivirus-transduced human HSC-enriched cell population, we observed eGFP-positive cells with clear hepatocyte morphology in the livers of animals. These eGFP-positive cells co-expressed human albumin, and reverse-transcription polymerase chain reaction (PCR) analysis demonstrated the presence of human albumin and -anti-trypsin mRNA. However, two antibodies against human mitochondria and human nuclei failed to mark eGFP-positive hepatocyte-like cells but did give clear staining of donor-derived hematopoietic cells. Subsequent fluorescent in situ hybridization (FISH) analysis revealed the presence of mouse Y chromosome in eGFP-positive hepatocyte-like cells. To resolve this discrepancy, we performed single-cell PCR analysis of microdissected eGFP-positive hepatocyte-like cells and found that they contained mostly mouse and little human genomic material. FISH analysis highlighting the centromeres of all human chromosomes revealed only few human chromosomes in these cells. From these results, we conclude that similar to their murine counterparts, human hematopoietic cells have the potential to fuse with resident host hepatocytes. Because no selective pressure is applied to retain the human genomic material, it is gradually lost over time, leading to a variable phenotype of the chimeric cells and making their detection difficult.

This article has been cited by other articles:

				V. Franceschini, S. Bettini, S. Pifferi, A. Rosellini, A. Menini, R. Saccardi, E. Ognio, R. Jeffery, R. Poulsom, and R. P. Revoltella Human Cord Blood CD133+ Stem Cells Transplanted to Nod-Scid Mice Provide Conditions for Regeneration of Olfactory Neuroepithelium After Permanent Damage Induced by Dichlobenil Stem Cells, April 1, 2009; 27(4): 825 - 835. [Abstract] [Full Text] [PDF]

				C. Nern, I. Wolff, J. Macas, J. von Randow, C. Scharenberg, J. Priller, and S. Momma Fusion of Hematopoietic Cells with Purkinje Neurons Does Not Lead to Stable Heterokaryon Formation under Noninvasive Conditions J. Neurosci., March 25, 2009; 29(12): 3799 - 3807. [Abstract] [Full Text] [PDF]

				N. Brezillon, D. Kremsdorf, and M. C. Weiss Cell therapy for the diseased liver: from stem cell biology to novel models for hepatotropic human pathogens Dis. Model. Mech., September 1, 2008; 1(2-3): 113 - 130. [Abstract] [Full Text] [PDF]

				D. A. Hess, T. P. Craft, L. Wirthlin, S. Hohm, P. Zhou, W. C. Eades, M. H. Creer, M. S. Sands, and J. A. Nolta Widespread Nonhematopoietic Tissue Distribution by Transplanted Human Progenitor Cells with High Aldehyde Dehydrogenase Activity Stem Cells, March 1, 2008; 26(3): 611 - 620. [Abstract] [Full Text] [PDF]

				Y N Kallis, M R Alison, and S J Forbes Bone marrow stem cells and liver disease Gut, May 1, 2007; 56(5): 716 - 724. [Full Text] [PDF]

				R. Poulsom, E. I. Prodromidi, C. D. Pusey, and H. T. Cook Cell therapy for renal regeneration--time for some joined-up thinking? Nephrol. Dial. Transplant., December 1, 2006; 21(12): 3349 - 3353. [Full Text] [PDF]