Reagents and Methods for Using Human Embryonic Stem Cells to Evaluate Toxicity of Pharmaceutical Compounds and Other Chemicals
First Claim
1. A method for identifying one or a plurality of cellular metabolites having a molecular weight of from about 10 to about 1500 Daltons that is differentially produced in human embryonic stem cells (hESCs) or hESC-derived lineage-specific cells contacted with a test compound, the method comprising the steps of:
- a) culturing hESCs or hESC-derived lineage-specific cells in the presence or absence of a test compound;
b) assaying one or a plurality of cellular metabolites having a molecular weight of from about 10 to about 1500 Daltons in hESCs or hESC-derived lineage-specific cells cultured in the presence and absence of the test compound; and
c) identifying at least one metabolite product having a molecular weight of from about 10 to about 1500 Daltons that is differentially produced in the cells in the presence or absence of the test compound.
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Abstract
The invention provides biomarker profiles of cellular metabolites and methods for screening chemical compounds including pharmaceutical agents, lead and candidate drug compounds and other chemicals using human embryonic stem cells (hESC) or lineage-specific cells produced therefrom. The inventive methods are useful for testing toxicity, particularly developmental toxicity and detecting teratogenic effects of such chemical compounds.
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Citations
54 Claims
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1. A method for identifying one or a plurality of cellular metabolites having a molecular weight of from about 10 to about 1500 Daltons that is differentially produced in human embryonic stem cells (hESCs) or hESC-derived lineage-specific cells contacted with a test compound, the method comprising the steps of:
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a) culturing hESCs or hESC-derived lineage-specific cells in the presence or absence of a test compound;
b) assaying one or a plurality of cellular metabolites having a molecular weight of from about 10 to about 1500 Daltons in hESCs or hESC-derived lineage-specific cells cultured in the presence and absence of the test compound; and
c) identifying at least one metabolite product having a molecular weight of from about 10 to about 1500 Daltons that is differentially produced in the cells in the presence or absence of the test compound. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 42, 43, 44, 49, 52)
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16. A method for screening a test compound to identify an effect of the compound on human embryonic stem cells (hESCs) or hESC-derived lineage-specific cells contacted with the test compound, the method comprising the steps of:
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a) culturing hESCs or hESC-derived lineage-specific cells in the presence or absence of a test compound b) assaying the hESCs or hESC-derived lineage-specific cells cultured in the presence and absence of the test compound for production of one or a plurality of cellular metabolites having a molecular weight of from about 10 to about 1500 Daltons; and
c) identifying test compounds that produce at least one cellular metabolite having a molecular weight of from about 10 to about 1500 Daltons that is differentially produced in the cells in the presence or absence of the test compound. - View Dependent Claims (17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 50, 53)
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31. A method for assaying a test compound for toxicity or teratogenicity to human embryonic stem cells (hESCs) or hESC-derived lineage-specific cells contacted with the test compound, the method comprising the steps of:
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a) culturing hESCs or hESC-derived lineage-specific cells in the presence or absence of a test compound b) assaying hESCs or hESC-derived lineage-specific cells cultured in the presence and absence of the test compound to identify one or a plurality of cellular metabolites having a molecular weight of from about 10 to about 1500 Daltons produced by hESCs contacted with a toxic or teratogenic compound; and
c) identifying test compounds wherein hESCs or hESC-derived lineage-specific cells produce one or a plurality of cellular metabolites having a molecular weight of from about 10 to about 1500 Daltons in the presence or absence of the test compound wherein said cellular metabolites are produced by hESCs or hESC-derived lineage-specific cells contacted with a toxic or teratogenic compound. - View Dependent Claims (32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 45, 51, 54)
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- 46. A biomarker profile for identifying a test compound as a toxic compound, wherein the biomarker profile comprises one or a plurality of cellular metabolites having a molecular weight of from about 10 to about 1500 Daltons that are differentially produced in human embryonic stem cells (hESCs) or hESC-derived lineage-specific cells contacted with a toxic compound or compounds.
Specification