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Development of Transplantable Engineered Graft by Organ Derived Acellular Frame

Higashi, Hisanobu1; Yagi, Hiroshi1; Tajima, Kazuki1; Abe, Yuta1; Hibi, Taizo1; Kitago, Minoru1; Shinoda, Masahiro1; Tomi, Masatoshi2; Mizoguchi, Hiroyuki3; Kitagawa, Yuko1

doi: 10.1097/

1Department of Surgery, Keio University, School of Medicine, Tokyo, Japan; 2Faculty of Pharmacy, Keio University, Tokyo, Japan; 3Lab. of Biochemistry and Molecular Biology, Osaka University, Graduate School and School of Pharmaceutical Sciences, Osaka, Japan.

Background: Stem cell technology has accelerated regenerative medicine approaches targeting the liver. However, some technical difficulties in scale-up or delivery of large amount of these cells still remain as a barrier of clinical application. To overcome these limitations, we have developed a tissue engineering approach using “de/recellularized organ frame”. The aim of this study was to generate native liver derived organ frame, which was filled with porcine hepatocytes or human induced pluripotent stem (iPS) cells. Its function and clinical utility was assessed by preclinical large animal model.

Methods: The decellularization protocol for porcine liver was re-optimized. Acellular liver frame was then filled with 1x109 of hepatocytes isolated from porcine liver or 5x108 of hepatocyte like cells derived from human iPS cells, co-seeding with porcine or human endothelial cells. The engineered grafts were transplanted into normal liver pigs or pigs with liver injury induced by retrorsine (RS) administration with 60% hepatectomy. Functional outcomes of the graft was assessed by angiography, H-E stein, Azan stein, SEM, immunostain, Bilirubin stein, blood test, and CYP gene expression profiling. 60% hepatectomized pigs without RS was designed as a control group.

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