Functional liver tissue can be grown in lymph nodes of mice and rescue them from lethal hepatic disease, reports Toshitaka Hoppo et al. in the February issue of Gastroenterology—lymph nodes therefore might someday be used as sites for hepatocyte transplantation in patients with end-stage liver disease.
Many patients with chronic hepatic damage have cirrhosis and fibrosis, which limit the potential for liver regeneration or repair. Hoppo et al. investigated alternative locations for growing liver tissue in mice with liver failure.
They isolated hepatocytes from wild-type mice and injected them into peritoneal cavities of mice deficient in fumarylacetoacetate hydrolase (Fah−/−), a model of the human liver disease tyrosinemia type I. Interestingly, the hepatocytes colonized and survived in lymph nodes, where they expanded at the expense of lymphocytes.
Ten weeks after transplantation, the mice had substantial improvements in serum levels of transaminases, bilirubin and amino acids. Most importantly, the hepatocytes in the lymph nodes rescued the mice from lethal hepatic failure.
Analysis of the hepatized lymph nodes showed that not only had the lymphocytes almost completely disappeared, but high endothelial venules (specialized post-capillary venules found in lymphoid tissue) were also missing after hepatocyte colonization. The high endothelial venules were replaced by large vessels that were similar (in histology and size) to those of a normal liver (see below figure), indicating adaptation of the vasculature to the newly generated hepatic tissue. Parial hepatectomy of the diseased liver expanded the mass of hepatized lymph nodes, indicating that homeostatic control of liver mass also affected the ectopic site.
Interestingly, when enough ectopic liver tissue grew to restore hepatic function, proliferation of hepatocytes stopped; 20–40 hepatized lymph nodes formed in each mouse, comprising about 70% of the original liver mass. Hoppo et al. did not observe complications associated with lymphadenopathy, such as ascites or lower-extremity edema. However, markers for reticular fibroblasts and reticular fibers, as well as for Kupffer cells, were missing from the hepatized lymph nodes. So, the architecture and cellular content of the ectopic liver differed from normal liver.
The authors propose that the highly vascularized nature of the lymph nodes supported the engrafment and massive expansion of the liver tissue. They stated “lymph nodes could be compared with a well-designed in vivo bioreactor, built for the rapid expansion of lymphocytes but retasked for colonization by hepatocytes.”
Further studies are needed to determine how the hepatocytes enter the lymph nodes, and whether human hepatic insufficiency provides a selective advantage for transplanted liver cells. No effective protocol has been established for hepatocyte repopulation of patients. However, Hoppo et al. propose that this methodology might be applied to patients with end-stage liver disease who cannot be treated by liver transplantation or regeneration.
Read the article online:
Hoppo T, Komori J, Manohar R, et al. Rescue of lethal hepatic failure by hepatized lymph nodes in mice. Gastroenterology 2011;140:656–666.e2.