Liver progenitor cells, their secretome and liver repair

Project Details

Description

Many chronic liver diseases can lead to hepatic dysfunction with organ failure, of which the prevalence in Europe is estimated to be approximately 29 million. Liver transplantation is the only validated therapy of end-stage liver disease, unfortunately problems of donor shortage still remain and a major challenge is to avoid patient death on the waiting list. Transplantation of isolated hepatocytes represents a treatment option for inborn errors of liver metabolism, to bridge unstable patients to transplantation or allows patients to recover from fulminant liver failure. However, the low liverengraftment rate and survival of transplanted hepatocytes hamper this procedure, highlighting the need for novel approaches to redress this problem. Besides improving hepatocyte transplantation, the field has also turned towards other sources of hepatocytes such as embryonic, induced or adult stem cells such as liver progenitor cells (LPCs) that can be expanded in vitro. Three major hurdles keep the liver progenitor field from translational breakthroughs:
i) expansion of LPCs while keeping their "stemness" features in vitro,
ii) complete in vitro differentiation towards mature hepatocytes and
iii) the demonstration that endogenous LPCs indeed participate in liver repair upon injury. The objective of this project is therefore to demonstrate and identify the instructive cues that influence LPCs or are produced by LPCs. We will approach this by:
i) evaluating the contribution of endogenous LPCs to liver cell replacement in vivo. We will inhibit the LPC activation and study the course of disease progression in different mouse models of liver injury,
ii) establishing the conditions that enable the expansion and differentiation of LPCs to allow an extensive analysis of those cells without isolating them daily, thereby also reducing laboratory animal use. Our approach is based on the use of decellularized injured mouse livers that will stimulate either proliferation or differentiation of LPCs,
iii) studying the therapeutic potential of mouse LPC secretome in mice with acute hepatic failure. Administration of the secretome of LPCs will be used to test a
possible beneficial effect of the LPC secretome on liver recovery, eventually leading to the identification of novel players that could mediate this response, iv) analysing the therapeutic potential of human LPCs and their secretome in liver repair. We will determine the therapeutic potential of human LPCs or their secretome by transplanting proliferating or differentiated LPCs into nude mice
with a liver injury, either alone or with their secretome. If successful, the developed tools and identified factors will improve culture conditions of LPCs, allowing LPC expansion or differentiation of LPCs towards mature hepatocytes in culture. This would alleviate the shortage of hepatocytes needed to perform hepatocyte transplantations in patients with end stage liver disease or genetic metabolic disorders. Additionally, pharmaceutical and biotechnology companies would benefit from this continuous supply of hepatocytes for their drug metabolism and toxicity studies and evaluation of hepatitis infection and anti-viral drug screenings.
AcronymIWT622
StatusFinished
Effective start/end date1/01/1331/12/16

Keywords

  • Fibrosis
  • Hepatic Stellate Cells
  • Histon (de)acetylation
  • Stellate cell activation
  • Liver Cell Transplantation
  • Liver Sinusoidal Cells
  • Portal hypertension
  • Sinusoidal Cells
  • cirrhosis
  • Cytoskeleton
  • Cell Biology
  • Fat-Storing Cells
  • NASH / NAFLD
  • Intermediate Filaments
  • liver stem / progenitor cells
  • autophagy
  • Flow Cytometry
  • Metabolic Syndrome

Flemish discipline codes in use since 2023

  • Morphological sciences
  • Oncology
  • Cytology
  • Multimedia processing
  • Immunology

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