Role of platelets on liver regeneration after 90% hepatectomy in mice

Background/Aims

Mortality after 90% partial hepatectomy in mice was associated with severe acute liver failure. Recently, we revealed that platelets have a strong promotional effect on hepatic regeneration. In the present study, we investigated the effect of thrombocytosis on liver regeneration after 90% hepatectomy in mice.

Methods

For thrombocytosis induction PEG-rHuMGDF was injected 5 days before operation. Hepatectomy, sparing only the caudate lobe, was performed in normal and thrombocytotic BALB/c mice. Survival rate, platelet number, liver weight/body weight ratio, proliferating cell nuclear antigen, serum parameters, signal transduction and overexpressed genes were examined.

Results

Platelet number was significantly higher in thrombocytotic group. All mice in normal group died within 30 h after hepatectomy. Survival rate in thrombocytotic group was 6/11 at 30 h and 3/11 one week after hepatectomy. Activation of Akt and STAT3 signaling pathways in thrombocytotic group was observed earlier and recognized to be stronger compared to normal group. Cell cycle, signaling pathways, metabolism and transport genes were significantly overexpressed in thrombocytotic group up to 24 h after hepatectomy.

Conclusions

Under the thrombocytotic condition, liver regeneration occurred even in 90% hepatectomized mice. Platelets contribute to cell cycle progression and metabolic pathways in addition to preventing acute liver failure.

Introduction

Among all organs the liver has a unique regeneration capacity after injury. It occurs due to the hyperplasia of the residual lobes and mitosis of the hepatocytes which are quiescent under normal conditions [1], [2], [3]. Liver regeneration (LR) has been a subject of scientific research, focusing on the replication mechanism, promoting, inhibiting factors and expressed genes [3], [4]. The most commonly used surgical experimental model of LR in mice is 70% partial hepatectomy (PH) [5]. Makino et al. in their study, which aimed to find a safe limit of experimental liver resection, revealed that an extra massive 90% PH was lethal for mice. The cause of death was associated with severe acute liver failure induced by small residual liver [6]. All 90% hepatectomized mice in that study died within 24 h while all 70% hepatectomized mice survived. Until now, 90% PH has been described as a perfect experimental model of acute liver failure in mice [6], [7].

In addition to substances responsible for haemostasis platelets contain various growth factors like HGF, IGF-1, TGFβ1, serotonin and PDGF which do not contribute to LR [8], [9]. Pioneering studies which connected LR with platelet growth factors established that platelets contain heat stabile substances which promote DNA synthesis in primary adult rat hepatocyte cultures [10]. Recently it was reported that platelet-derived serotonin mediates liver regeneration [11], [12]. In our previous studies we revealed that platelets stimulate hepatocyte proliferation in vitro and in vivo models [13], [14]. In the present study we continue the investigation of platelets’ role in LR using a thrombocytosis model in mice after 90% PH which was previously considered as fatal.