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AssigneeCambridge Enterprise Limited
InventorsLudovic Vallier, Sheikh Tamir Rashid, Nicholas Hannan, Hsin-Hua Cho
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This invention relates to the induction of hepatic differentiation by culturing induced pluripotent stem (iPS) cells in an endoderm induction medium to produce a population of anterior definitive endoderm (ADE) cells and then culturing the population of ADE cells in a hepatic induction medium to produce a population of hepatic progenitor cells, which may be optionally differentiated into hepatocytes. The endoderm induction medium is a chemically defined medium which has fibroblast growth factor activity, stimulates SMAD2 and SMAD3 mediated signalling pathways and SMAD1, SMAD5 and SMAD9 mediated signalling pathways, and inhibits phosphatidylinositol 3-kinase (PI3K) and glycogen synthase kinase 3β (GSK3β); and the hepatic induction medium is a chemically defined medium which stimulates SMAD2 and SMAD3 mediated signalling pathways. These methods may be useful, for example, in producing hepatocytes and hepatic progenitor cells for cell-based therapies or disease modelling.
A method for inducing hepatic differentiation comprising;
A method according to any one of the preceding claims wherein the endoderm induction medium comprises a second TGFβ ligand which stimulates SMAD1, SMAD5 and SMAD9 mediated signalling pathways.
A method according to any one of the preceding claims wherein the endoderm induction medium comprises a PI3K inhibitor and a GSK3β inhibitor.
A method according to any one of the preceding claims wherein the hepatic induction medium comprises a first TGFβ ligand which stimulates SMAD2 and SMAD3 mediated signalling pathways.
A method according to any one of the preceding claims wherein step (ii) comprises:
A method according to any one of the preceding claims further comprising;
A method according to any one of the preceding claims comprising admixing the population of hepatic progenitor cells or hepatocytes with a pharmaceutically acceptable excipient.
A method according to any one of the preceding claims wherein the iPS cells are human iPS cells.
A method according to any one of the preceding claims wherein said iPS cells have been passaged 30 times or less.
A method according to any one of the preceding claims wherein the iPS cells are derived from fibroblasts obtained from an individual.
A method according to any one of the preceding claims wherein the iPS cells are derived from cells obtained from an individual with damaged or dysfunctional liver tissue and the hepatocytes in the population display a normal phenotype.
Dependencies are inferred from the claim text.