Intramuscular transplantation of engineered hepatic tissue constructs corrects acute and chronic liver failure in mice.
OBJECTIVE
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.
Navarro-Alvarez
Nalu
N
Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, Shikata-cho, Okayama, Japan.
Soto-Gutierrez
Alejandro
A
Chen
Yong
Y
Caballero-Corbalan
Jose
J
Hassan
Wael
W
Kobayashi
Satoru
S
Kondo
Yoshitaka
Y
Iwamuro
Masaya
M
Yamamoto
Kazuhide
K
Kondo
Eisaku
E
Tanaka
Noriaki
N
Fox
Ira J
IJ
Kobayashi
Naoya
N
D000818:Animals; D002460:Cell Line; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000378:metabolism / Q000637:transplantation* / Q000648:ultrastructure; D006801:Humans; D007273:Injections, Intramuscular; D017093:Liver Failure / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D017114:Liver Failure, Acute / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D016031:Liver Transplantation; D051379:Mice; D046529:Microscopy, Electron, Transmission; D018482:Muscle, Skeletal; D057139:Nanofibers; D036103:Nanotechnology; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds; D016042:Transplantation, Heterotopic