Development of a novel human 3D in vitro model for evaluating new anti-fibrotic drugs

Abstract:

The discovery and development of anti-fibrotic therapies remains heavily reliant on animal testing. There is an urgent need to develop robust and relevant in vitro models to support the identification and preclinical evaluation of potential new anti-fibrotic drugs(1). To this end, we have developed and characterised a novel human 3D liver co-culture model using our proprietary OrganDOTâ„¢ platform. These liver OrganDOTs (human hepatocytes, Kupffer cells and stellates) not only maintain viability and functionality for up to 4 weeks in culture, but can also be treated with TGFbeta1 to induce a fibrotic phenotype. The TGFbeta1-treated OrganDOT cultures show a decrease in hepatocyte function and a concomitant increase in fibrogenic gene expression (COL1A1, ACTC2, CTGF, OPN, TIMP-2), hyaluronic acid secretion, and collagen deposition (collagen I immunostaining). Furthermore, co-administration of an ALK5 inhibitor was able to completely prevent these fibrotic changes and rescue the functionality of the cultures. These data demonstrate the potential utility of this in vitro model for testing the efficacy of new anti-fibrotic drug candidates or for research into the mechanism of stellate cell activation and fibrosis induction.

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