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Project properties

Title	Molecular mechanisms behind blood platelet-induced liver regeneration
Keywords	surgery liver regeneration platelet proliferation
Researchers	prof. dr. J.A. Lisman
Nature of the research	In vitro (mainly cell culture), in vivo (liver resection experiments in rodents with analysis by histology and electron microscopy)
Fields of study	surgery gastroenterology

Background / introduction

The liver has a unique capacity to regenerate. Following a partial hepatectomy in animals or humans, the liver is able to fully regenerate to its original size. However, after a liver resection in humans, some patients fail to regenerate, which may eventually lead to death or requirement for a liver transplantation. At present, no therapeutic strategies to stimulate liver regeneration are available. Recently, blood platelets have been identified as crucial players in liver regeneration in animals and humans, and stimulation of blood platelet-mediated liver regeneration may be a novel therapeutic approach to treat patients with a failing regenerative response. The mechanisms responsible for blood platelet-mediated liver regeneration are poorly understood, but may involve release of liver-directed growth factors that are stored in platelets.

Research question / problem definition

We aim to investigate 1) the relevance of growth factors stored within the platelet for platelet-mediated liver regeneration, 2) the relevance of de novo synthesis of these growth factors. Although platelets lack a nucleus, it has been recently described that platelets are able to synthesize proteins from mRNA, and it may be that de novo synthesize of liver-directed growth factors is required for efficient liver regeneration, 3) the role of platelet uptake by hepatocytes for liver regeneration. We have recently found that platelets enter hepatocytes by yet unidentified mechanisms. We aim to elucidate these mechanisms and at the same time assess whether uptake is required for stimulation of hepatocyte mitosis.

Workplan

Using in vitro models we will determine whether platelets are able to synthesize liver-directed growth factors, and by using RNA silencing approaches test whether de novo synthesis of these growth factors is required for stimulation of hepatocyte growth, both in healthy and diseases hepatocytes. We will study the processes involved in platelet uptake by hepatocytes in cell culture models, and identify to which parts of the cell the platelet travels before releasing its contents, and determine whether these processes are required for platelet-mediated stimulation of hepatocyte mitosis. Finally, using rodent models of liver resection, we will determine platelet trafficking within the regenerating liver over time by using liver tissue taken at various time points after liver resection which will be analyzed by histology and electron microscopy. Also, the relevance of findings from the in vitro studies will be tested in these in vivo models.

References
Science. 2006;312(5770):104-7, Ann Surg. 2010 Feb;251(2):300-6, Semin Thromb Hemost. 2010;36(2):170-4.