The disclosure provides a method for producing hepatocytes or hepatic progenitor cells; a method for suppressing hepatocyte aging using a drug causing histone hyperacetylation; a hepatocyte anti-aging agent; a method for increasing hepatocyte plasticity; and a drug for increasing hepatocyte plasticity.

The invention relates to differentiation methods for progenitor cells, e.g. mammalian epithelial stem cells, differentiation media for use in said methods, organoids and cells obtainable by said methods and uses, including therapeutic uses, thereof.

Provided are methods for inducing differentiation of pluripotent stem cells, e.g., induced pluripotent stem cells, to form definitive endoderm. Also provided are methods for producing more committed endodermal cells such as hepatoblasts or hepatocytes.

The invention provides a method for constructing a hepatic progenitor cell-like cell bank, including successively performing following processes to human primary hepatocyte cultures from different donor sources: transformation-culture, cryopreservation treatment, proliferation-culture, a first subculture treatment, virus infection, a second subculture treatment, continuous selection-culture and continuous subculture. In the method for constructing a heterogenous immortal hepatic progenitor cell-like cell bank of the present invention, the human primary hepatocyte culture of each of the donor sources is transformation-cultured before the proliferation-culture, which is beneficial in endowing the human primary hepatocyte cultures with good proliferation performance. Once combined with subsequent controlling of culture parameter, the immortal hepatic progenitor cell-like cell lines obtained from different donor sources may have good in vitro proliferation ability. The invention also provides an application of the hepatic progenitor cell-like cell bank and cell lines obtained by the construction method.

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.

There is disclosed a preparation of extracellular vesicles derived from human liver stem cells, preferably from a non-oval human progenitor cell line that expresses hepatic cell markers, which is capable of reducing the senescence of a population of senescent cells, as measured in a SA-β-galactosidase-based cellular senescence assay. Also disclosed are therapeutic applications of the preparation of extracellular vesicles derived from human liver stem cells according to the invention. Therapeutic applications include the reduction of cellular senescence, e.g. in an vitro or ex vivo method, as well as the therapeutic treatment of diseases and conditions known to be related to ageing and cellular senescence, such as for example atherosclerosis, diabetes mellitus type 2, asthenia, and others.

This disclosure relates generally to methods for generating small hepatocyte progenitor cells (SHPCs) and hematopoietic progenitor cells (HPCs) from human embryonic stem cells, and hematopoietic progenitor cells from primary human endothelial cells and cell lines populations of small hepatocyte progenitor cells and hematopoietic progenitor cells, and uses thereof.

Provided is a composition and an application thereof. The composition is used to prepare a medium for inducing differentiation of human pluripotent stem cells to liver precursor cells. By means of screening active components, optimizing the composition ratio and adding a GSK3-beta inhibitor, a Nodal activator, a BMP activator, a BMP inhibitor and a Hedgehog activator, human pluripotent stem cells are induced to differentiate to liver precursor cells. The process is simple and efficient, the content of positive cells is high, and the cost of cell differentiation is reduced. The invention can be used for research and application in drug development and regenerative medicinal treatment, and has broad application prospects.

The present disclosure provides methods and kits for the differentiation of stem cells into relevant liver cell lineages, as well as methods of using the relevant liver cell lineages in screening for a cellular response, a phenotype and in the treatment of a condition. In one embodiment, stem cells are first differentiated into cells of the definitive endoderm lineage, which are differentiated into posterior foregut (PFG) lineage cells by one or more of retinoic acid activators and/or one or more inhibitors of transforming growth factor-β (TGFβ). An additional embodiment provides a method for the differentiation of posterior foregut lineage cells into liver bud progenitors (LB) by one or more activators of TGFβ signalling, and/or one or more modulators of Wnt signalling, and/or one or more activators of cyclic AMP/PKA signaling; and a further embodiment provides a method for the differentiation of liver bud progenitors into hepatic progenitors by one or more inhibitors of TGFβ signalling and/or fibroblast growth factor (FGF) inhibitors and/or one or more Notch inhibitors. Another embodiment discloses the differentiation of hepatic progenitors into hepatocyte-like cells or perivenous hepatocyte-like cells by one or more of Notch inhibitors and/or activators of glucocorticoid signalling and/or one or more activators of insulin signalling and/or one or more of ascorbic acid signalling activators and/or additional factors. Methods and kits for maintaining LB in self renewal state, hepatocyte-like cells in perivenous or periportal state, as well as surface markers for LB and mid/hindgut (MHG) cells are also disclosed.

The current invention concerns isolated liver progenitor cells, cell lines thereof, cell populations comprising such and compositions comprising such wherein the liver progenitor cells are HLA-E positive. In addition, the invention concerns methods of preparing these liver progenitor cells.