Intramuscular transplantation of engineered hepatic tissue constructs corrects acute and chronic liver failure in mice
Received 1 February 2009; received in revised form 16 July 2009; accepted 20 July 2009. published online 08 December 2009.
Background & Aims
Transplantation of isolated hepatocytes holds great promise as an alternative to whole organ liver transplantation. For treatment of liver failure, access to the portal circulation has significant risks and intrahepatic hepatocyte engraftment is poor. In advanced cirrhosis, transplantation into an extrahepatic site is necessary and intrasplenic engraftment is short-lived. Strategies that allow repeated extrahepatic infusion of hepatocytes could improve the efficacy and safety of hepatocyte transplantation for the treatment of liver failure.
Methods
A non-immunogenic self-assembling peptide nanofiber (SAPNF) was developed as a three-dimensional scaffold and combined with growth factors derived from a conditionally immortalized human hepatocyte cell line to engineer a hepatic tissue graft that would allow hepatocyte engraftment outside the liver.
Results
The hepatic tissue constructs maintained hepatocyte-specific gene expression and functionality in vitro. When transplanted into skeletal muscle as an extrahepatic site for engraftment, the engineered hepatic grafts provided life-saving support in models of acute, fulminant, and chronic liver failure that recapitulates these clinical diseases.
Conclusions
SAPNF-engineered hepatic constructs engrafted and functioned as hepatic tissues within the muscle to provide life-sustaining liver support. These engineered tissue constructs contained no animal products that would limit their development as a therapeutic approach.
1Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan
2Marion Bessin Liver Research Center, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Avenue, Ullmann 523, Bronx, NY 10461, USA
3Departments of Oncology, Radiology & Clinical Immunology, Division of Clinical Immunology, The Rudbeck Laboratory, Uppsala University, Uppsala SE-751 85, Sweden
4Department of Pathophysiology-Periodontal Science, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan
53-D Matrix Japan, Ltd., 3-2-4 Kojimachi, Chiyoda-ku, Tokyo 102-0083, Japan
6Department of Internal Medicine, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan
7Department of Pathology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan
8Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
Corresponding author. Address: Department of Gastroenterological Surgery, Transplant and Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. Tel./fax: +81 86 235 7485.
† Present address: Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical, Boston, MA 02129, USA.
‡ Present address: Department of Surgery, Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, MA 02114, USA.
ABSTRACT