Glycoprotein 130-dependent pathways in host hepatocytes are important for liver repopulation in mice

Abstract

Hepatocyte transplantation (HT) is still restricted by the limited amount of transplantable cells. Therefore, a better understanding of the mechanisms involved in cellular engraftment, proliferation, and in vivo selection is important. Here we aimed to evaluate the role of the interleukin 6 (IL-6)/glycoprotein 130 (gp130) system for liver repopulation. Mice carrying a conditional hepatocyte-specific deletion of the common IL-6 signal transducer gp130 (gp130 ⌬hepa ) were used for HT. First, we compared bone marrow transplantation (BMT), partial hepatectomy (PH), and retrorsine treatment of recipient mice to optimize the in vivo selection of transplanted hepatocytes. BMT combined with PH was sufficient to induce a 30-fold increase in the number of transplanted donor hepatocytes, whereas additional retrorsine pretreatment led to an up to 40-fold increase. Next, the influence of gp130 signaling in hepatocytes on cell selection was evaluated. Wild-type (WT) hepatocytes repopulated WT recipients at the same rate as gp130 ⌬hepa cells. In contrast, liver repopulation by transplanted cells was enhanced in gp130 ⌬hepa recipient mice. This was associated with higher proliferation of donor hepatocytes and enhanced apoptosis in gp130 ⌬hepa recipient livers. Additionally, the acute phase response was strongly induced after HT in WT recipients but blunted in gp130 ⌬hepa recipients. As a result, significantly more liver remodeling, evidenced by stronger hepatic stellate cell activation and collagen accumulation, was found in gp130 ⌬hepa mice after HT. In conclusion, the HT model established here can be efficiently applied to investigate cell-specific mechanisms in liver repopulation. Moreover, we have shown that gp130-dependent pathways in host hepatocytes are important for controlling liver repopulation. Liver Transpl 16:23-32, 2010.

Hepatic Tissue Environment in NEMO-Deficient Mice Critically Regulates Positive Selection of Donor Cells after Hepatocyte Transplantation

“…In our previous reports, we showed that BMT usually is required for successful repopulation after HT [19], [21]. These data were confirmed in NEMO Δhepa mice, where we observed selection of transplanted hepatocytes only after preceding-BMT.…”

“…Hepatocyte transplantation is currently considered as a promising alternative, especially once the yield and outcome of this technique can be improved. In our previous studies we demonstrated the feasibility of HT and identified responsible factors for donor cell selection in this model [13], [19].…”

Hepatocyte growth factor/c-Met signalling is important for the selection of transplanted hepatocytes

“…Recipient animals were treated according to a previously established protocol in our laboratory 17. This includes host conditioning by BMT and subsequent retrorsine (24 mg/kg) application followed by partial hepatectomy (figure 1A).…”

“…Both mechanisms are considered to be relevant for the repopulation process after hepatocyte transplantation 17. BrdU incorporation analysis was performed (figure 3A) to investigate proliferation.…”

“…We therefore used our previously established protocol of sequential BMT, the application of the pyrrazol-alkaloide retrorsine and partial hepatectomy,17 which ensures the selection of transplanted hepatocytes. It is thus interesting that we observed no selection of transplanted cells at all when c-Met-deficient donor cells were used, even though recipients were preconditioned as described.…”