Role of Monocyte Chemoattractant Protein (MCP)-1 in Liver Regeneration

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DESCRIPTION (provided by the applicant): Incomplete liver regeneration is an obstacle to recovery from liver disease and for patients who receive grafts through living-donor liver transplantation. Improved understanding of the mechanisms that regulate liver regeneration will facilitate the development of new strategies to improve recovery from liver disease and survival after transplantation. The purpose of this study is to investigate the mechanisms by which monocyte chemoattractant protein (MCP)-1 regulates liver regeneration. MCP-1 is a small, secreted protein in the family of C-C chemokines. In the liver, Kupffer cells, hepatic stellate cells, and sinusoidal endothelial cells produce MCP-1, which functions through autocrine and paracrine pathways to promote chemotaxis and/or activation of nonparenchymal cells. Research shows that patients who express high levels of MCP-1 are more prone to hepatic inflammation and fibrosis, but little is known about the role of MCP-1 during liver regeneration. Using a mouse model system of liver regeneration induced by 70% partial hepatectomy, we recently made the novel discovery that liver regeneration is impaired in the absence of MCP-1. We hypothesize that MCP-1 is required to stimulate nonparenchymal cells to produce the cytokines and growth factors that promote hepatocyte proliferation during regeneration. Such soluble mediators include tumor necrosis factor (TNF)-??and interleukin (IL)-6, which are produced by Kupffer cells, and hepatocyte growth factor (HGF), which is produced primarily by stellate cells. Another important mediator is vascular endothelial growth factor (VEGF), which induces the proliferation of sinusoidal endothelial cells and also stimulates stellate cells to produce HGF. The specific aims of this study are 1) to determine if MCP-1 is required for the production of Kupffer cell-derived TNF??and IL-6 during regeneration; 2) to identify how MCP-1 contributes to stellate cell activation and HGF production during regeneration; and 3) to characterize how MCP-1 modulates VEGF production and VEGF receptor signaling during regeneration. To test each aim, wild type and MCP-1 knockout mice will be anesthetized, subjected to surgery, and euthanized at relevant times after surgery. Data will be compared between wild type and MCP-1 knockout mice to determine how MCP-1 contributes to the activation of nonparenchymal cells and the subsequent production of soluble mediators that regulate liver regeneration. PUBLIC HEALTH RELEVANCE: The proposed work could establish an important role for monocyte chemoattractant protein (MCP)-1 in regulating liver regeneration. Results from this project could provide the rationale for developing new strategies to promote MCP-1 signaling during recovery from liver disease and transplantation procedures. Finally, this project provides an opportunity for undergraduates at Boise State University to participate in biomedical research and gain an appreciation of the complex regulatory mechanisms that govern regeneration.