Cardiomyocytes from induced pluripotent stem cells from patients and methods of use thereof

摘要

Human somatic cells obtained from individuals with a genetic heart condition are reprogrammed to become induced pluripotent stem cells (iPS cells), and differentiated into cardiomyocytes for use in analysis, screening programs, and the like.

主权项

1. A method for cardiac disease-relevant screening of a candidate agent, the method comprising:
(a) contacting the candidate agent with an isolated population of one or more cardiomyocytes or a panel of cardiomyocytes differentiated from one or more induced human pluripotent stem cells (iPS cells) comprising at least one allele encoding a mutation associated with a cardiac disease; and (b) determining the effect of the candidate agent on one or more phenotypes exhibited by one or more cardiomyocytes within the isolated population of cardiomyocytes or within the panel of cardiomyocytes wherein the one or more phenotypes are associated with dilated cardiomyopathy and are selected from the group consisting of: (a) relative to a cardiomyocyte produced from an induced pluripotent stem cell derived from a normal subject (“normal iPSC-CM”), an initial positive chronotropic effect in response to positive inotropic stress that later becomes negative with characteristics of failure; (b) a decreased inotropic activity compared to a normal iPSC-CM; (c) a decreased chronotropic activity compared to a normal iPSC-CM; (d) a decreased contractile force compared to a normal iPSC-CM; (e) a gene expression profile that differs from a gene expression profile of a normal iPSC-CM; (f) calcium transients that are smaller than calcium transients displayed by a normal iPSC-CM; (q) a weaker ability to resist mechanical stimulation as compared to a normal iPSC-CM; (h) cessation of spontaneous contraction in response to norepinephrine stimulation; (i) a higher frequency of punctate distribution of sarcomeric alpha-actin in comparison to a normal iPSC-CM; and (j) increased sarcomeric disorganization in response to contractile stimulation when compared to a normal iPSC-CM.