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Novel population of hepatocytes derived via definitive endoderm (de-hep) from human blastocysts stem cells

a technology of endoderm and blastocysts, which is applied in the field of new hepatocyte population derived via definitive endoderm (dehep) from human blastocysts stem cells, can solve the problems of large death rate, limited efficacy of this procedure, and major burden on the health care system, and achieves the effect of increasing the percentag

Inactive Publication Date: 2010-07-29
CELLARTIS AB (SE)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention relates to a method for preparing hepatoblast-like cells and hepatocyte-like cells from human blastocyst-derived stem cells. The method involves inducing the stem cells to develop into definitive endoderm cells, and then further culturing them to obtain DE-hep progenitor cells and DE-hep cells. The DE-hep cells exhibit characteristics of hepatocytes and can be used for drug transport and drug metabolism enzyme testing. The invention also provides a cell population comprising DE-hep progenitor cells and DE-hep cells."

Problems solved by technology

Liver failure and end-stage liver diseases are responsible for a huge amount of deaths around the world and is a major burden on the health care system.
However, the efficacy of this procedure is limited and connected to many complications such as infection or rejection.
Liver transplantation also suffers from shortage of available donor organs and the treated patients will very often be referred to lifelong immunosuppression.
Unfortunately, the complexity and function of the liver is not mirrored by any cell type available today.
The availability of primary human liver cells is very limited and the cells are also known to rapidly loose their normal phenotype and functional properties (i.e. within 24 hours) when used for in vitro applications.
Thus, many tests are still performed using animal material, even though liver metabolism is known to be species specific and thereby generating difficulties in predicting liver metabolism and toxicity in another species than the one tested.
A complication in the study of endoderm is that mammals possess extraembryonic endoderm.

Method used

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  • Novel population of hepatocytes derived via definitive endoderm (de-hep) from human blastocysts stem cells
  • Novel population of hepatocytes derived via definitive endoderm (de-hep) from human blastocysts stem cells
  • Novel population of hepatocytes derived via definitive endoderm (de-hep) from human blastocysts stem cells

Examples

Experimental program
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Effect test

example 1

Starting Material

[0220]The starting material for the present invention is suitably pluripotent undifferentiated hBS cells, such as undifferentiated hBS cell lines. Such material can be obtained from Cellartis AB, www.cellartis.com. Cellartis AB is the largest source of defined hBS cell lines world wide and has more than 30 hBS cell lines and subclones available today. Two of the cell lines are listed in the National Institutes of Health (NIH) Human Embryonic Stem Cell Registry, http: / / stemcells.nih.gov / research / registry / and 20 in the UK Stem Cell Bank. Additionally, Cellartis can provide hBS cell lines approved for research use by major markets such as Japan, Germany and France. For the present invention hBS cell line SA002, SA002.5, SA034, SA167, SA181, SA348 and SA461 were used specifically. Characteristics of the hBS cells recommended as starting material are the following: positive for alkaline phosphatase, SSEA-3, SSEA-4, TRA 1-60, TRA 1-81, Oct-4, negative for SSEA-1, telomer...

example 2

Inducing Undifferentiated hBS Cells into DE and Further into Functional Hepatocytes

[0224]Undifferentiated hBS cells were maintained and propagated in vitro. At day 4-7 after passage undifferentiated hBS cell colonies were treated according to a basic differentiation program. Each step in this protocol is characterized by key components that are crucial;

Stage I, Definitive endoderm (DE): low serum and Activin A

Stage II, DE-Hep progenitor cells: members of the TGFbeta superfamily of proteins, especially BMP4

Stage III, functional DE-Hep cells: HGF

Changes in growth factor exposure time, concentration, various combinations of them and length of treatment have been tested

[0225]An overview of the basic method and variations is presented in FIG. 1a. The undifferentiated hBS cells are induced to DE by incubation with Activin A (100 ng / ml) for 3-5 days in RPMI Advanced medium or DMEM medium or a comparable medium (stage I, day 0). The medium is changed every day. The first day of Activin A in...

example 3

Morphology of Definitive Endoderm, Stage I

[0265]Activin A treatment was associated to morphological changes and distinct differentiation pattern of the colonies. After 3-5 days, treated by an Activin A-containing medium, cells gathered together and formed a ring of epithelial cells around the colony (FIG. 2). Those homogenous growing cells expanded over the plate and could be passaged to a Mouse feeder layer containing plate.

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Abstract

The present disclosure relates to a novel hepatocyte-like cell progenitor and / or a novel hepatocyte-like cell derived via definitive endoderm from human blastocyst-derived stem (hBS) cells, to a method for the preparation of such cells and to the potential use of such cells in, e.g., pharmaceutical drug discovery and development, toxicity testing, cell therapy and medical treatment. In particular is presented a definitive endoderm derived hepatocyte-like cell with important liver-expressed marker genes and important metabolizing enzymes, as well as drug transporters.

Description

FIELD OF THE INVENTION[0001]The present invention relates to a novel hepatoctye-like cell population derived via definitive endoderm from human blastocyst-derived stem (hBS) cells, to a method for the preparation of such cells and to the potential use of such cells in e.g. pharmaceutical drug discovery and development, toxicity testing, cell therapy and medical treatment. The cells are denoted DE-hep cells herein.[0002]Furthermore, the DE-Hep cells exhibits properties of functional human hepatocytes which make them attractive for use in in vitro studies of hepatogenesis such as early liver development processes or liver-regenerative disorders or malformations.BACKGROUND OF THE INVENTION[0003]Pluripotent human stem cells are expected to revolutionize the accessibility to a variety of human cell types. The possibility to propagate pluripotent human blastocyst-derived stem (hBS) cells and subsequently differentiate them into the desired target cell types will provide a stable and virtu...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12Q1/02C12N5/071
CPCC12N5/067C12N2501/113C12N2501/115C12N2501/12C12N2506/02C12N2501/16C12N2501/237C12N2501/39C12N2501/415C12N2501/155A61P1/16
Inventor HEINS, NICOBROLEN, GABRIELLAKUPPERS-MUNTHER, BARBARA
Owner CELLARTIS AB (SE)
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