Abstract
Portal vein ligation (PVL) induces liver growth prior to resection. Associating liver partition and portal vein ligation (PVL plus transection=ALPPS) or the addition of the prolyl-hydroxylase inhibitor dimethyloxalylglycine (DMOG) to PVL both accelerate growth via stabilization of HIF-α subunits. This study aims at clarifying the crosstalk of hepatocytes (HC), hepatic stellate cells (HSC) and liver sinusoidal endothelial cells (LSEC) in accelerated liver growth. In vivo, liver volume, HC proliferation, vascular density and HSC activation were assessed in PVL, ALPPS, PVL+DMOG and DMOG alone. Proliferation of HC, HSC and LSEC was determined under DMOG in vitro. Conditioned media experiments of DMOG-exposed cells were performed. ALPPS and PVL+DMOG accelerated liver growth and HC proliferation in comparison to PVL. DMOG alone did not induce HC proliferation, but led to increased vascular density, which was also observed in ALPPS and PVL+DMOG. Activated HSC were detected in ALPPS, PVL+DMOG and DMOG, again not in PVL. In vitro, DMOG had no proliferative effect on HC, but conditioned supernatant of DMOG-treated HSC induced VEGF-dependent proliferation of LSEC. Transcriptome analysis confirmed activation of proangiogenic factors in hypoxic HSC. Hypoxia signaling in HSC induces VEGF-dependent angiogenesis. HSC play a crucial role in the cellular crosstalk of rapid liver regeneration.
Highlights
Portal vein ligation (PVL) induces liver growth prior to resection
One animal died within 24 h after PVL, one animal died intraoperatively in the ALPPS group due to bleeding during hilar dissection and injury to the hepatic artery and one in the PVL+DMOG group within 24 h due to intraoperative hematoma resulting in a perioperative mortality rate of 12% (n = 3/25 for all animals)
Hepatocyte proliferation in ALPPS and PVL+DMOG was demonstrated by an increased number of Ki-67 positive nuclei, while PVL and DMOG alone did not affect hepatocyte proliferation rate at 72 h (Fig. 1G)
Summary
Associating liver partition and portal vein ligation (PVL plus transection=ALPPS) or the addition of the prolyl-hydroxylase inhibitor dimethyloxalylglycine (DMOG) to PVL both accelerate growth via stabilization of HIF-α subunits. It has been demonstrated that HIFα subunit stabilizers such as prolyl-hydroxylase inhibitors (PHI) like DMOG, which induce hypoxia signaling, accelerate liver regeneration in rodents, and that factors increasing tissue oxygenation abrogate this effect[13,14]. Hypoxia signaling in the regenerating liver accelerates liver regeneration, but it is unclear which cell type (hepatocytes or non-parenchymal cells) transduces oxygen sensing into a proliferative signal in ALPPS It is not known what a short-term treatment of the normal liver with HIFα-stabilizing drugs does without portal vein rerouting. Based on previous reports[18,19], we hypothesized that HSC play a crucial role in hypoxia sensing and cellular crosstalk
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