Intramuscular transplantation of engineered hepatic tissue constructs corrects acute and chronic liver failure in mice

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.

Abbreviations: SAPNF, self-assembling peptide nanofiber, ELISA, enzyme-linked immunoabsorbent assay, ECM, extracellular matrix, HTX, hepatocyte transplantation, ALF, acute liver failure, FLF, fulminant liver failure, CLF, chronic liver failure, SCID/mice, severe combined immunodeficiency mice, 3-D, three-dimensional, OLT, orthotopic liver transplantation, CM, condition media, IM, intramuscular

Keywords: Hepatocytes, SAPNF, Extracellular matrix, Hepatocyte transplantation, Acute liver failure, Chronic liver failure, Hepatic tissue engineering