Cell Reports (Jun 2020)
Assembly and Function of a Bioengineered Human Liver for Transplantation Generated Solely from Induced Pluripotent Stem Cells
- Kazuki Takeishi,
- Alexandra Collin de l’Hortet,
- Yang Wang,
- Kan Handa,
- Jorge Guzman-Lepe,
- Kentaro Matsubara,
- Kazutoyo Morita,
- Sae Jang,
- Nils Haep,
- Rodrigo M. Florentino,
- Fangchao Yuan,
- Ken Fukumitsu,
- Kimimasa Tobita,
- Wendell Sun,
- Jonathan Franks,
- Evan R. Delgado,
- Erik M. Shapiro,
- Nicolas A. Fraunhoffer,
- Andrew W. Duncan,
- Hiroshi Yagi,
- Tomoji Mashimo,
- Ira J. Fox,
- Alejandro Soto-Gutierrez
Affiliations
- Kazuki Takeishi
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
- Alexandra Collin de l’Hortet
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Yang Wang
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Hepatobiliary Surgery, Peking University People’s Hospital, Beijing 100044, China
- Kan Handa
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Jorge Guzman-Lepe
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Kentaro Matsubara
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Kazutoyo Morita
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Sae Jang
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Nils Haep
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Rodrigo M. Florentino
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Physiology and Biophysics, Universidade Federal de Minas Gerais, Belo Horizonte 31270-010, Brazil
- Fangchao Yuan
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
- Ken Fukumitsu
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Kimimasa Tobita
- Department of Bioengineering and Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15201, USA
- Wendell Sun
- LifeCell Corporation, Branchburg, NJ 08876, USA
- Jonathan Franks
- Center for Biologic Imaging, University of Pittsburgh Medical School, Pittsburgh, PA 15261, USA
- Evan R. Delgado
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219-3110, USA; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Erik M. Shapiro
- Department of Radiology, Michigan State University, East Lansing, MI 48824, USA
- Nicolas A. Fraunhoffer
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Facultad de Ciencias de la Salud, Carrera de Medicina, Universidad Maimónides, Ciudad Autónoma de Buenos Aires and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad Autónoma de Buenos Aires, Buenos Aires 1001, Argentina
- Andrew W. Duncan
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219-3110, USA; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Hiroshi Yagi
- Department of Surgery, School of Medicine, Keio University, Tokyo 160-8582, Japan
- Tomoji Mashimo
- Division of Animal Genetics, Laboratory Animal Research Center, Institute of Medical Science, University of Tokyo, Tokyo 158-8557, Japan
- Ira J. Fox
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219-3110, USA; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Surgery, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA 15224, USA
- Alejandro Soto-Gutierrez
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219-3110, USA; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15213, USA; Corresponding author
- Journal volume & issue
-
Vol. 31,
no. 9
Abstract
Summary: The availability of an autologous transplantable auxiliary liver would dramatically affect the treatment of liver disease. Assembly and function in vivo of a bioengineered human liver derived from induced pluripotent stem cells (iPSCs) has not been previously described. By improving methods for liver decellularization, recellularization, and differentiation of different liver cellular lineages of human iPSCs in an organ-like environment, we generated functional engineered human mini livers and performed transplantation in a rat model. Whereas previous studies recellularized liver scaffolds largely with rodent hepatocytes, we repopulated not only the parenchyma with human iPSC-hepatocytes but also the vascular system with human iPS-endothelial cells, and the bile duct network with human iPSC-biliary epithelial cells. The regenerated human iPSC-derived mini liver containing multiple cell types was tested in vivo and remained functional for 4 days after auxiliary liver transplantation in immunocompromised, engineered (IL2rg−/−) rats.
