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Project grant

Modelling liver fibrosis using human Induced Pluripotent Stem Cells

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At a glance

Completed
Award date
December 2015 - May 2018
Grant amount
£242,470
Principal investigator
Dr Ludovic Vallier
Institute
University of Cambridge

R

  • Replacement
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Contents

Application abstract

End-stage liver cirrhosis is one of the most common causes of mortality in modern countries and can only be treated by liver transplantation, which is strongly limited by the lack of organ donors and the side effects of immunosuppressive treatment. Therefore, the development of new therapeutics against liver diseases represents a global health challenge and one of the main objective for the pharmaceutical industry.

However, the lack of relevant, physiological and high throughput in vitro system to model liver fibrosis represents a major issue. Current in vitro models of the fibrotic liver consist in cell cultures, precision slice biopsies, and whole organ perfusion systems. 2D culture systems lack functional cell-to-cell interactions and anatomical structures needed to reveal mechanistic details of disease involved in fibrosis, while perfusion and biopsy based models cannot persist long enough to accurately model fibrotic progression. Consequently, most studies are based on animal models which can lack the physiological relevance to human diseases and which are not compatible with high throughput platform necessary for drug screening. 

Here, we propose to use of human Induced Pluripotent Stem Cells (hIPSCs) to establish an in vitro model for liver fibrosis. For that, hIPSCs will be differentiated into cell types relevant for the disease including hepatocytes, macrophages, cholangiocytes, and stellate cells. The resulting cells will embedded in a 3-D scaffold-based culture system compatible with high trough put analyses. Then different etiologies will be modeled including liver fibrosis induced by ethanol, tetrachloride and alpha-1 antitrypsin deficiency. The resulting system will be validated by direct comparison with results obtained in mouse model for liver injury. This project will pave the way for the development of new in vitro model for the study of fibrosis in a diversity of organs and will ultimately allow the development of new therapies.

Publications

  1. Fourrier A et al. (2020). Regenerative cell therapy for the treatment of hyperbilirubinemic Gunn rats with fresh and frozen human induced pluripotent stem cells-derived hepatic stem cells. Xenotransplantation 27(1):e12544. doi: 10.1111/xen.12544
  2. Grandy R et al. (2019). Modeling Disease with Human Inducible Pluripotent Stem Cells. Annual Review of Pathology 14:449-468. doi: 10.1146/annurev-pathol-020117-043634
  3. Hurrell T et al. (2019). A proteomic time course through the differentiation of human induced pluripotent stem cells into hepatocyte-like cells. Scientific Reports 9:3270. doi: 10.1038/s41598-019-39400-1
  4. Serrano F et al. (2019). A Novel Human Pluripotent Stem Cell-Derived Neural Crest Model of Treacher Collins Syndrome Shows Defects in Cell Death and Migration. Stem cells and development 28(2):81-100. doi: 10.1089/scd.2017.0234
  5. Yiangou L et al. (2019). Method to Synchronize Cell Cycle of Human Pluripotent Stem Cells without Affecting Their Fundamental Characteristics. Stem Cell Reports 12(1):165–179. doi: 10.1016/j.stemcr.2018.11.020
  6. Alberts R et al. (2018). Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis. Gut 67(8):1517-1524. doi: 10.1136/gutjnl-2016-313598 
  7. Hurrell T et al. (2018). Proteomic Comparison of Various Hepatic Cell Cultures for Preclinical Safety Pharmacology. Toxicological Sciences 164(1):229-239. doi: 10.1093/toxsci/kfy084
  8. Rashidi H et al. (2018). 3D human liver tissue from pluripotent stem cells displays stable phenotype in vitro and supports compromised liver function in vivo. Archives of Toxicology 92(10):3117-3129. doi: 10.1007/s00204-018-2280-2
  9. Segeritz CP et al. (2018). hiPSC hepatocyte model demonstrates the role of unfolded protein response and inflammatory networks in α1-antitrypsin deficiency. Journal of Hepatology 69(4):851-60. doi: 10.1016/j.jhep.2018.05.028
  10. Yiangou L et al. (2018). Human Pluripotent Stem Cell-Derived Endoderm for Modeling Development and Clinical Applications. Cell stem cell 22(4):485-499. doi: 10.1016/j.stem.2018.03.016