2013 - CTS 2013 Congress

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Oral Communications 2

6.4 - Assembly of functional transplantable liver grafts

Presenter: Alejandro, Soto-Gutierrez, Pittsburgh, United States
Authors: Ken Fukumitsu1, Kan Handa1, Kentaro Matsubara1, Jorge Guzman-Lepe1, Kimimasa Tobita1, Chris Hobson1, Thomas Gilbert1, Michael Oertel1, Hiroshi Yagi1, Alejandro Soto-Gutierrez1

Assembly of functional transplantable liver grafts

Ken Fukumitsu1, Kan Handa1, Kentaro Matsubara1, Jorge Guzman-Lepe1, Kimimasa Tobita1, Chris Hobson1, Thomas Gilbert1, Michael Oertel1, Hiroshi Yagi1, Alejandro Soto-Gutierrez1

1Pathology, University of Pittsburgh, Pittsburgh, PA, United States


About thirty million people in the US undergo a liver disorder for different causes and about 28,000 deaths are registered annually in the US due to liver disease. To date the only definitive treatment is liver transplantation, however, a major reason of liver related deaths is the limited donor pool. In the last decade, the paradigm in organ transplantation has shifted away from immune suppressive regiments toward tolerance induction and the need to expand the donor pool through organ engineering. This project aims to use discarded donor livers as natural scaffolds to constitute complete functional livers grafts to be transplantable with success by employing techniques from tissue engineering and cell/organ transplantation. 
We have developed optimized protocols for whole rat liver decellularization and designed critical criteria for organ-specific matrix quality based on ECM structure and components, DNA content and proteomics studies. Moreover, we have generated reproducible systems/protocols for recellularization with freshly isolated hepatocytes. Ultimately reconstruction of liver grafts in vitro also requires the addition of liver non-parenchymal cells, thus, we have designed complete vasculature and bile duct recellularization protocols. In order to evaluate and optimize different cell seeding protocols of vasculature (portal and central vein) and bile duct recellularization, we have designed different systems for histological and imaging evaluation based on micro CT and MRI technology. This system allows us to perform serial evaluations of the recellularization protocols for further optimizations. We found that up to 80-90% of the vessels in the whole liver were adequately recellularized with microvascular endothelial cells and about 60-80% of the bile ducts were adequately recellularized with bile duct cells. Moreover, endothelial and hepatic function was evaluated over time (endothelial: LDL metabolism and tPA responsive secretion; hepatic: albumin synthesis, urea secretion and total bile salts secretion) after complete recellularization of liver grafts and demonstrated that the newly engineered liver grafts remain functional. The development of methodologies for liver graft assembly has the potential to become a novel platform for future sophisticated organ engineering techniques that incorporates several different cell types and may ultimately lead to development of entire organs in vitro for transplantation drug development and biological studies.

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