Chimeric liver transplantation reveals interspecific graft remodelling
Author(s): ,
Christian Toso
Affiliations:
Hepato-Pancreato-Biliary Centre, Geneva University Hospitals, Geneva, Switzerland
Corresponding authors. Address: Geneva University Hospitals, Department of Surgery, Rue Gabrielle Perret-Gentil, 1204 Genève, Switzerland.
,
Stéphanie Lacotte
Affiliations:
Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
,
Hiromitsu Nakauchi
Affiliations:
Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
,
Laura Rubbia-Brandt
Affiliations:
Division of Clinical Pathology, Department of Pathology and Immunology, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
,
Toshihiro Kobayashi
Affiliations:
Section of Mammalian Transgenesis, Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki, Japan
,
Tomoyuki Yamaguchi
Affiliations:
Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan
,
Lorenzo A. Orci
Affiliations:
Hepato-Pancreato-Biliary Centre, Geneva University Hospitals, Geneva, Switzerland
,
Vaihere Delaune
Affiliations:
Hepato-Pancreato-Biliary Centre, Geneva University Hospitals, Geneva, Switzerland
,
Philippe Morel
Affiliations:
Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
,
Quentin Gex
Affiliations:
Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
,
Florence Slits
Affiliations:
Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
,
Elizabeth M. Wilson
Affiliations:
Yecuris Corporation, Portland, OR, USA
,
Sandrine Vijgen
Affiliations:
Division of Clinical Pathology, Department of Pathology and Immunology, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
,
Andrea Peloso
Affiliations:
Hepato-Pancreato-Biliary Centre, Geneva University Hospitals, Geneva, Switzerland
Graziano Oldani
Affiliations:
Hepato-Pancreato-Biliary Centre, Geneva University Hospitals, Geneva, Switzerland
Corresponding authors. Address: Geneva University Hospitals, Department of Surgery, Rue Gabrielle Perret-Gentil, 1204 Genève, Switzerland.
EASL LiverTree™. Toso C. Nov 1, 2018; 256701
Prof. Christian Toso
Prof. Christian Toso
Contributions Biography
Journal Abstract
References
Graphical abstract

Graphical abstract

Mouse livers repopulated with rat hepatocytes and transplanted into rats lead to long-term survival. Chimeric liver grafts undergo recipient-oriented remodeling of hepatocytes, cholangiocytes and endothelial cells. Liver size is not limited to its original size in the donor species.

Background & Aims

A major limitation in the field of liver transplantation is the shortage of transplantable organs. Chimeric animals carrying human tissue have the potential to solve this problem. However, currently available chimeric organs retain a high level of xenogeneic cells, and the transplantation of impure organs needs to be tested.

Methods

We created chimeric livers by injecting Lewis rat hepatocytes into C57Bl/6Fah−/−Rag2−/−Il2rg−/− mice, and further transplanted them into newly weaned Lewis rats (45 ± 3 g) with or without suboptimal immunosuppression (tacrolimus 0.6 mg/kg/day for 56 or 112 days). Control donors included wild-type C57Bl/6 mice (xenogeneic) and Lewis rats (syngeneic).

Results

Without immunosuppression, recipients of chimeric livers experienced acute rejection, and died within 8 to 11 days. With immunosuppression, they all survived for >112 days with normal weight gain compared to syngeneic controls, while all xenogeneic controls died within 98 days due to rejection with Banff scores >6 (p = 0.0014). The chimeric grafts underwent post-transplant remodelling, growing by 670% on average. Rat hepatocytes fully replaced mouse hepatocytes starting from day 56 (absence of detectable mouse serum albumin, histological clearance of mouse hepatocytes). In addition, rat albumin levels reached those of syngeneic recipients. Four months after transplantation of chimeric livers, we observed the development of diffuse mature rat bile ducts through transdifferentiation of hepatocytes (up to 72% of cholangiocytes), and patchy areas of portal endothelium originating from the host (seen in one out of five recipients).

Conclusions

Taken together, these data demonstrate the efficacy of transplanting rat-to-mouse chimeric livers into rats, with a high potential for post-transplant recipient-oriented graft remodelling. Validation in a large animal model is still needed.

Lay summary

Chimeric animals are composed of cells from different species. Chimeric animals carrying human tissue have the potential to increase the availability of transplantable organs. We transplanted rat-to-mouse liver grafts into newly weaned rats. The chimeric grafts underwent post-transplant remodelling with rat hepatocytes replacing all mouse hepatocytes within 56 days. In addition, we observed the post-transplant development of diffuse mature rat bile ducts through the transformation of hepatocytes, and patchy areas of portal endothelium originating from the host. These data demonstrate the efficacy of transplanting rat-to-mouse chimeric livers into rats, with a high potential for post-transplant graft remodelling.

Keyword(s)
Liver transplantation, Chimera, Chimeric graft, Remodelling, Xenotransplantation
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