Rescue of lethal hepatic failure by hepatized lymph nodes in mice.
OBJECTIVE
Hepatocyte transplantation is a potential therapeutic approach for liver disease. However, most patients with chronic hepatic damage have cirrhosis and fibrosis, which limit the potential for cell-based therapy of the liver. The development of an ectopic liver as an additional site of hepatic function represents a new approach for patients with end-stage liver disease. We investigated the development and function of liver tissue in lymph nodes in mice with liver failure.


METHODS
Hepatocytes were isolated from 8- to 12-week-old mice and transplanted by intraperitoneal injection into 8- to 12-week-old fumarylacetoacetate hydrolase mice (Fah(-/-)), a model of the human liver disease tyrosinemia type I. Survival was monitored and the locations and functions of the engrafted liver cells were determined.


RESULTS
Lymph nodes of Fah(-/-) mice were colonized by transplanted hepatocytes; Fah(+) hepatocytes were detected adjacent to the CD45(+) lymphoid cells of the lymphatic system. Ten weeks after transplantation, these mice had substantial improvements in serum levels of transaminases, bilirubin, and amino acids. Homeostatic expansion of donor hepatocytes in lymph nodes rescued the mice from lethal hepatic failure.


CONCLUSIONS
Functional ectopic liver tissue in lymph nodes rescues mice from lethal hepatic disease; lymph nodes therefore might be used as sites for hepatocyte transplantation.
McGowan Institute for Regenerative Medicine, Department of Pathology, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania 15219, USA.
Toshitaka
T
Hoppo
Junji
J
Komori
Rohan
R
Manohar
Donna Beer
DB
Stolz
Eric
E
Lagasse
D000596:Amino Acids / Q000097:blood; D000818:Animals; D001663:Bilirubin / Q000097:blood; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D022781:Hepatocytes / Q000637:transplantation*; D006867:Hydrolases / Q000235:genetics; D017493:Leukocyte Common Antigens / Q000032:analysis; D017093:Liver Failure / Q000209:etiology / Q000601:surgery*; D008198:Lymph Nodes / Q000502:physiology*; D008214:Lymphocytes / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000637:Transaminases / Q000097:blood; D020176:Tyrosinemias / Q000150:complications / Q000235:genetics / Q000601:surgery
D000596:Amino Acids; D000637:Transaminases; C502724:Fahd2a protein, mouse; D006867:Hydrolases; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse; D001663:Bilirubin