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First published online March 13, 2008
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Submitted on August 21, 2007
Accepted on February 29, 2008

TISSUE-SPECIFIC STEM CELLS

Embryonic Porcine Liver as a Source for Transplantation: Advantage of Intact Liver Implants Over Isolated Hepatoblasts in Overcoming Homeostatic Inhibition by the Quiescent Host Liver

Helena Katchman 1, Orna Tal 2, Smadar Eventov-Friedman 2, Elias Shezen 2, Anna Aronovich 2, Dalit Tchorsh 2, Sivan Cohen 2, Alexander Shtabsky 3, Gil Hecht 2, Benjamin Dekel 2, Enrique Freud 4, Yair Reisner 2*

1 Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel; Department of Pathology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
2 Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
3 Department of Pathology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
4 Department of Pediatric Surgery, Schneider Children's Medical Center, Petach Tikvah 49202, Israel.

* To whom correspondence should be addressed. E-mail: yair.reisner{at}weizmann.ac.il.


  Abstract

Cell therapy as an alternative for orthotopic liver transplantation represents a major challenge, since negligible proliferation of isolated hepatocytes occurs after transplantation due to the stringent homeostatic control displayed by the host liver. Thus, different modalities of liver injury as part of the pre-transplant conditioning are a prerequisite for this approach.

The major objective of the present study was to test whether xenotransplantation of pig fetal liver fragments, in which potential cell-cell and cell-stroma interactions are spared, might afford more robust growth and proliferation compared to isolated pig fetal hepatoblasts.

After transplantation into SCID mice, fetal liver tissue fragments exhibited marked growth and proliferation, in the setting of a quiescent host liver, compared to isolated fetal hepatoblasts harvested at the same gestational age (E28). The proliferative advantage of fetal pig liver fragments was clearly demonstrated by immunohistochemical and morphometric assays and was observed not only after implantation into the liver but also into the extra-hepatic sites such as the spleen and the sub-renal capsule. The presence of all types of non-parenchymal liver cells that is crucial for normal liver development and regeneration was demonstrated in the implants.

Conclusions: Preservation of the three dimensional structure in pig fetal liver fragments enables autonomous proliferation of transplanted hepatic cells in the setting of a quiescent host liver, without any requirement for liver injury in the pre-transplant conditioning. The marked proliferation and functional maturation exhibited by the pig fetal liver fragments suggests it could afford a preferable source for transplantation.

 Key Words. Cellular therapy, Fetal stem cells, Hepatic stem cells, Microenvironment, Xenogeneic stem cell transplantation






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