Maturation of hepatocyte-like cells derived from human pluripotent stem cells
First Claim
1. A method for promoting the maturation of in vitro derived human hepatocyte-like cells, the method comprising:
- exposing said human hepatocyte-like cells to an activator of a retinoic acid responsive receptor selected from the group consisting of 9-cis-retinoic acid, 13-cis-retinoic acid, SR11237, and combinations thereof, thereby promoting the maturation of said human hepatocyte-like cells by increasing the gene expression of one or more markers for mature hepatocytes selected from the group consisting of adult isoforms of HNF4α
, CYP1A2, CYP2B6, CYP2C9, CYP3A4, CYP3A5, CAR, GSTA1-1, NTCP and PXR;
wherein the human hepatocyte-like cells exposed to said activator of a retinoic acid responsive receptor do not exhibit gene and protein expression of Oct4.
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Abstract
The present invention relates to directed differentiation and maturation of hepatocyte-like cells. In particular, the present invention relates to exposure of hepatocyte-like cells to an activator of a retinoic acid responsive receptor, such as retinoic acid (RA), optionally in combination with an inhibitor of GSK-3 (Glycogen synthase kinase 3) or activator of Wnt signalling and/or with the overlay of the cells with one or more components characteristic of the mammalian extracellular matrix (matrix overlay). The present invention also relates to exposure of hepatocyte-like cells to an activator of a retinoic acid responsive receptor, such as retinoic acid (RA), optionally in combination with an inhibitor of a cycline dependent kinase (CDK) and/or with the overlay of the cells with one or more components characteristic of the mammalian extracellular matrix (matrix overlay). The hepatocyte-like cells obtained in accordance with the present invention show a phenotype which is more similar to that of primary hepatocytes than previously shown.
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22 Claims
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1. A method for promoting the maturation of in vitro derived human hepatocyte-like cells, the method comprising:
exposing said human hepatocyte-like cells to an activator of a retinoic acid responsive receptor selected from the group consisting of 9-cis-retinoic acid, 13-cis-retinoic acid, SR11237, and combinations thereof, thereby promoting the maturation of said human hepatocyte-like cells by increasing the gene expression of one or more markers for mature hepatocytes selected from the group consisting of adult isoforms of HNF4α
, CYP1A2, CYP2B6, CYP2C9, CYP3A4, CYP3A5, CAR, GSTA1-1, NTCP and PXR;
wherein the human hepatocyte-like cells exposed to said activator of a retinoic acid responsive receptor do not exhibit gene and protein expression of Oct4.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)
Specification