Provided is a method of differentiating a pluripotent stem cell of mammalian origin into a desired cell type by predicting the direction of cell differentiation to be caused by induction of expression of a transcription factor. A human gene expression correlation matrix using human cells has been newly created, and further, it has been confirmed that human pluripotent stem cells can be differentiated into a desired cell type by introducing, into the human pluripotent stem cells, a transcription factor cocktail selected from the matrix.

Disclosed are methods of treating or reducing the occurrence of a steatohepatitis disorder. The disorder may include, for example, NASH, parenteral nutrition associated liver disease (PNALD), or genetic forms of liver disease. The method may comprise the step of administering a composition comprising obeticholic acid to an individual in need thereof.

Provided herein is a model system for liver fibrosis, including a liver extracellular matrix, and a combination of mammalian liver cells (e.g., primary liver cells) on the matrix. In some embodiments, the combination of liver cells includes: (a) liver progenitor cells, (b) Kupffer cells, and (c) hepatic stellate cells. Methods of making the model system and methods of use of the model system for screening active agents are also provided.

Provided is a method of differentiating a pluripotent stem cell of mammalian origin into a desired cell type by predicting the direction of cell differentiation to be caused by induction of expression of a transcription factor. A human gene expression correlation matrix using human cells has been newly created, and further, it has been confirmed that human pluripotent stem cells can be differentiated into a desired cell type by introducing, into the human pluripotent stem cells, a transcription factor cocktail selected from the matrix.

This application describes liver stem cells (LSC), and differentiated hepatocytes, cholangiocytes, and 3D cellular structures derived therefrom. Methods for producing LSC and mature, differentiated hepatocytes and cholangiocytes in culture are provided. Also provided are cell culture systems and cell culture media for producing a homogenous population of liver stem cells that remain in an undifferentiated state over multiple passages in culture. The LSC and methods are useful for producing homogenous populations of hepatocytes and cholangiocytes for downstream applications. The LSC can be transplanted into subjects to treat liver diseases.

Provided is a method for preparing functional hepatic (progenitor) cells or functional small intestinal epithelial (progenitor) cells, comprising the step of culturing an isolated cell population comprising hepatic (progenitor) cells or small intestinal epithelial (progenitor) cells in the presence of an antibiotic. Also, provided is a substantially homogeneous isolated cell population comprising functional hepatic progenitor cells, wherein an expression level of CYP3A4 in the functional hepatic progenitor cells is increased by at least 5 times the expression level thereof in a HeaRG.sup.(R) cell line.

The present invention encompasses engineered nucleases which recognize and cleave a recognition sequence within the int22h-1 sequence of a Factor VIII gene. The present invention also encompasses methods of using such engineered nucleases to make genetically-modified cells, and the use of such cells in a pharmaceutical composition and in methods for treating hemophilia A. Further, the invention encompasses pharmaceutical compositions comprising engineered nuclease proteins, nucleic acids encoding engineered nucleases, or genetically-modified cells of the invention, and the use of such compositions for treating of hemophilia A.

The present invention provides a system for artificially inducing and regulating tissue interactions among multiple tissues. A construct for transplantation into a living body, which comprises a structure and a cell mass linked to each other, the structure being an object having a three-dimensional structure and capable of mimicking or resembling a structure and/or a function of the living body.

The invention is directed to methods for culturing cells so that the cells are induced to differentiate into cells that express a hepatic stellate phenotype. The invention is also directed to cells produced by the methods of the invention. The cells are useful, among other applications, for treatment of liver deficiencies, liver metabolism studies, and liver toxicity studies, fibrogenic studies, or to support hepatocyte function in co-culture setting.

The present disclosure provides multipotent endoderm spheroid progenitor cells, liver organoids, intestinal organoids, and pancreatic spheroids, and methods for producing same from stem and progenitor cells.