2013 - CTS 2013 Congress
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Oral Communications 5
12.2 - Ectopic hepatocyte transplantation into the peri-hepatic and mesenteric lymph nodes: preliminary data in a pre-clinical large animal model
Presenter: Eric, Lagasse, Pittsburgh, United States
Authors: Paulo Fontes1,2, Junji Komori1,2, Roberto Lopez1,2, Eric Lagasse1,2
Ectopic hepatocyte transplantation into the peri-hepatic and mesenteric lymph nodes: preliminary data in a pre-clinical large animal model
Paulo Fontes1,2, Junji Komori1,2, Roberto Lopez1,2, Eric Lagasse1,2
1Surgery, University of Pittsburgh, Pittsburgh, PA, United States; 2Pathology, University of Pittsburgh, Pittsburgh, PA, United States
Introduction: Liver transplantation continues to be the only effective therapy for end-stage-liver disease (ESLD). Unfortunately, over 30% of the patients with ESLD initially considered as potential transplant candidates are unsuitable for liver transplantation due to additional medical conditions. This population lacks an effective therapeutic option that would address both the control of their portal hypertension (PH) and the subsequent enhancement of their functional hepatocellular mass (HCM). This protocol was developed to create a reliable site for hepatocyte transplantation in patients receiving transjugular intrahepatic portosystemic shunt (TIPS) as part of their minimally invasive therapy for PH, since TIPS can induce subsequent hepatic atrophy and progressive liver failure.
Methods: A group of 5 Landrace pigs (~70kg) underwent a left hepatectomy (LH). The right portal vein was subsequently ligated (RPVL) in the recipients (n=3) immediately after the initial LH. Hepatocytes were obtained from the left liver lobe and were transplanted into the lymph nodes (LN) by direct injection. Three perihepatic (PH) and over 10 mesenteric (MT) LN were infused with the same technique. These animals were followed up for 30 days. A subsequent group of animals (n=2) had a full portacaval shunt (PCS) after the initial LH. The main portal vein was fully ligated at the hepatic hylum and reimplanted in the lower inferior vena cava as previously described. The first animal was followed up for 30 days and the second animal for 60 days.
Results: All the animals survived the operative procedures, but displayed a transient weight loss with reversible mild to moderate hepatocellular damage. The RPVL group (n=3) had moderate signs of hepatic encephalopathy (HE), treated with Lactulose. The PCS group (n=2) had moderate to severe signs of HE. Liver function tests (LFTs) showed a progressive pattern of liver damage when the 2 groups were compared. The PCS group showed a higher yield of hepatic engraftment in LN and a higher proliferation index when compared to the RPVL group. The final hepatocellular mass obtained in the ectopic sites was higher in the PCS group followed up for 60 days.
Conclusions: Ectopic hepatocyte engraftment in both the PH and MT lymph nodes can be successfully obtained in an autologous pre-clinical large animal model when a partial hepatectomy followed by liver devascularization procedures are combined. The degree of liver injury has a direct impact in the subsequent level of cell engraftment and proliferation. Ectopic liver mass can be macroscopically identified within the LN while displaying normal parenchymal architecture. In spite having a full PCS, the animals showed signs of progressive liver regeneration, contrary to the progressive liver atrophy previously seen in dogs and primates. Ectopic hepatocyte engraftment into the LN followed the same pattern as previously described in mice models [1 & 2].
[1] Hoppo, T., Komori, J., Manohar, R., Stolz, D. B. & Lagasse, E. Rescue of lethal hepatic failure by hepatized lymph nodes in mice. Gastroenterology 2011, 140:656-666.
[2] Komori, J., Boone, L., DeWard, A., Hoppo, T. & Lagasse, E. The mouse lymph node as an ectopic transplantation site for multiple tissues. Nature biotechnology 2012, 30:976-983.
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