Abstract
Human induced pluripotent stem cells (iPSCs) have emerged as an effective platform for regenerative therapy, disease modeling, and drug discovery. iPSCs allow for the production of limitless supply of patient-specific somatic cells that enable advancement in cardiovascular precision medicine. Over the past decade, researchers have developed protocols to differentiate iPSCs to multiple cardiovascular lineages, as well as to enhance the maturity and functionality of these cells. Despite significant advances, drug therapy and discovery for cardiovascular disease have lagged behind other fields such as oncology. We speculate that this paucity of drug discovery is due to a previous lack of efficient, reproducible, and translational model systems. Notably, existing drug discovery and testing platforms rely on animal studies and clinical trials, but investigations in animal models have inherent limitations due to interspecies differences. Moreover, clinical trials are inherently flawed by assuming that all individuals with a disease will respond identically to a therapy, ignoring the genetic and epigenomic variations that define our individuality. With ever-improving differentiation and phenotyping methods, patient-specific iPSC-derived cardiovascular cells allow unprecedented opportunities to discover new drug targets and screen compounds for cardiovascular disease. Imbued with the genetic information of an individual, iPSCs will vastly improve our ability to test drugs efficiently, as well as tailor and titrate drug therapy for each patient.
Highlights
The groundbreaking discovery by Shinya Yamanaka and colleagues that a set of four transcription factors (Oct4/Sox2/c-Myc/Klf4) can induce reprogramming of somatic cells to induced pluripotent stem cells has revolutionized the field of biomedical research, providing an accessible, versatile, and adaptable platform for precision medicine (Takahashi et al 2007). iPSCs generated from an individual can subsequently be differentiated to a wide variety of functional somatic cells, which can be used for cell or cell-free therapy for regenerative medicine, in vitro patient-specific disease modeling, drug testing, toxicity screening, and threedimensional organ/organoid construction (Shi et al, 2017) (Fig. 1)
By screening a library of polymers comprised of poly-«-caprolacton (PCL), polyethylene glycol, and carboxylated PCL, Chun et al (2015) found that culturing iPSC-derived CM (iPSC-CM) on 4% polyethylene glycol–96% PCL resulted in high contractility and mitochondrial function of the cells, as well as more mature gene expression patterns, including induction of MLC2v and isoform switching from slow skeletal troponin I (ssTnI) to the postnatal form cardiac troponin I (cTnI)
Marfan syndrome is a heritable connective tissue disorder characterized by mutations in the FBN1 gene and manifested in development of thoracic aortic aneurysm (Granata et al, 2017). iPSC-vascular smooth muscle cell (vSMC) from Marfan Syndrome patients recapitulated in vitro the pathologic presentation of the disease, such as abnormal extracellular matrix degradation and aberrant transforming growth factor (TGF)-b signaling and apoptosis of vSMCs
Summary
Abstract——Human induced pluripotent stem cells (iPSCs) have emerged as an effective platform for regenerative therapy, disease modeling, and drug discovery. Drug therapy and discovery for cardiovascular disease have lagged behind other fields such as oncology. We speculate that this paucity of drug discovery is due to a previous lack of efficient, reproducible, and translational model systems. Existing drug discovery and testing platforms rely on animal studies and clinical trials, but investigations in animal models have inherent limitations due to interspecies differences. With everimproving differentiation and phenotyping methods, patient-specific iPSC-derived cardiovascular cells allow unprecedented opportunities to discover new drug targets and screen compounds for cardiovascular disease. Imbued with the genetic information of an individual, iPSCs will vastly improve our ability to test drugs efficiently, as well as tailor and titrate drug therapy for each patient
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