Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 72 (1), 320-342

Patient and Disease-Specific Induced Pluripotent Stem Cells for Discovery of Personalized Cardiovascular Drugs and Therapeutics

Affiliations
Review

Patient and Disease-Specific Induced Pluripotent Stem Cells for Discovery of Personalized Cardiovascular Drugs and Therapeutics

David T Paik et al. Pharmacol Rev.

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.

Figures

Fig. 1.
Fig. 1.
Applications of human iPSCs for precision medicine. Human iPSCs are differentiated to functional cardiovascular cells, providing an effective platform for patient-specific disease modeling, cell-based therapy, cell-free therapy, drug testing and screening, and bioengineered tissue construction. First, iPSC-derived cardiovascular cells can recapitulate patient-specific clinical phenotype in vitro, resulting in accurate genotype-to-phenotype correlation. iPSC-derived cells allow elucidation of patient-specific disease mechanisms, enabling drug screening and toxicity testing that are unique to the individual’s genetic and epigenetic makeup. iPSC-derived cells are also a source of cell-based therapy, allowing a patient’s own cells to be transplanted to the damaged tissue. In addition, exosomes and microRNAs secreted from patient-specific iPSC-derived cells allow them to be used for cell-free therapeutic purposes. Lastly, iPSC-derived cardiovascular cells can be engineered to create three-dimensional organoids or organ-like mimics of the heart or the blood vessels for advanced disease modeling. Overall, the risk of tumorigenicity and poor cell survival rate remain as challenges to be addressed.
Fig. 2.
Fig. 2.
Generation of cardiovascular cells from iPSCs. Somatic cells such as dermal fibroblasts or peripheral blood mononuclear cells isolated from individual patients can be reprogrammed to iPSCs via viral delivery of the four Yamanaka transcription factors (OCT4+, SOX2+). Most commonly, iPSCs are pushed to precardiac mesodermal lineage (KDR+, MESP1+) via GSK-3β inhibition, and then differentiated to cardiac progenitor cells (ISL1+, NKX2-5+) by canonical Wnt signaling inhibition. Functional cardiomyocytes (TNNT2+, ACTN2+), smooth muscle cells (CNN1+, MYH11+), or endothelial cells (CDH5+, PECAM1+) are generated by treatment with unique sets of growth factors and small molecules. Epicardial cells (WT1+, TBX18+) can also be generated from cardiac progenitor cells, which can then be differentiated to cardiac fibroblasts (POSTN+, DDR2+). Generation of endocardial cells (NFATC1+), either from cardiac progenitors or endothelial progenitors, is still under development. Recently, methods to generate atrial, ventricular, and nodal cardiomyocytes have been described. To date it is not clear whether specialized subtypes of endothelial cells or stromal cells can be made from iPSCs.
Fig. 3.
Fig. 3.
Drug screening and testing using patient-specific iPSCs. Patient-specific iPSCs provide a platform for personalized drug screening and testing. iPSCs generated from individual patients are differentiated into cardiovascular cells of interest and subjected to drug treatment in vitro. High-throughput methods allow functional characterization of the cells during or after drug treatment, from which responders vs. nonresponders and the side effects of the drug are identified. This information allows informed feedback to the patients regarding the drug’s efficacy and toxicity based on the individual responses to the drug. As such, patient-specific iPSC-based drug screening and testing provide accurate genotype-to-phenotype correlation that results in precise drug discovery and reduces the stressful and costly trial-and-error process for the patients, not to mention significantly reducing the cost of health care.
Fig. 4.
Fig. 4.
Cardiotoxic effects of cancer therapies. Although a number of targeted and untargeted cancer therapies have shown efficacy in cancer treatment, these therapies also cause cardiotoxic effects that can result in profound cardiovascular complications. Chemotherapies, including anthracyclines such as doxorubicin, tyrosine kinase inhibitors, Her2-targeted therapies, and proteosome inhibitors, are associated with vascular dysfunction and CM damage that can lead to heart failure. Platinum-based therapies, microtubule inhibitors, and radiation therapy have also been linked to arrhythmias and pericardial disease. The pathobiology or the disease mechanisms of such cardiotoxic effects of various cancer therapies have not been elucidated and must be addressed in a patient-specific manner.
Fig. 5.
Fig. 5.
Elucidating mechanisms of doxorubicin-induced cardiotoxicity. Doxorubicin has shown cardiotoxicity for some patients. The patient-specific disease mechanisms of doxorubicin-induced cardiotoxicity remain poorly understood, and the direct and indirect effects of doxorubicin on CMs have not been clarified. Previous studies demonstrated that susceptibility of TOP2B to its target genes is dynamically modulated by doxorubicin. Using iPSC-derived CMs from doxorubicin-sensitive and nonsensitive patients, the transcriptional machinery of TOP2B can be determined by combining chromatin immunoprecipitation-seq, RNA-seq, transposase-accessible chromatin-seq, and immunoprecipitation–mass spectrometry. Cross-analysis of RNA-seq and chromatin immunoprecipitation-seq will further allow identification of direct target genes of TOP2B, which can be confirmed by chromatin immunoprecipitation-seq of TOP2B in human heart tissue. Verification of cardiac-specific target genes of TOP2B will lead to effective patient-specific therapeutics to combat doxorubicin-induced cardiotoxicity.
Fig. 6.
Fig. 6.
Multifaceted etiology of complex cardiovascular diseases. Cardiovascular diseases, such as hypertension and vasculopathies, and cardiometabolic diseases from diabetic conditions are complex in nature, with highly multifaceted disease etiology. The known causal factors of disease include, but are not limited to, the following: genetic predisposition, exposure to environmental pollutants, stress, diet and microbiome changes, smoking, and daily routines such as aerobic activities. To best model such complex diseases, a combined analysis of transcriptome, metabolome, epigenome, and function of patient-specific iPSC-derived cells challenged with the factors in question must be performed. The results of these meta-analyses will provide precise characterization of the patient’s disease phenotype that optimizes the design of patient-specific therapeutics.

Similar articles

See all similar articles

References

    1. Abe J, Martin JF, Yeh ETH. (2016) The future of onco-cardiology: we are not iust “side effect hunters”. Circ Res 119:896–899. - PMC - PubMed
    1. Abou-Saleh H, Zouein FA, El-Yazbi A, Sanoudou D, Raynaud C, Rao C, Pintus G, Dehaini H, Eid AH. (2018) The march of pluripotent stem cells in cardiovascular regenerative medicine. Stem Cell Res Ther 9:201. - PMC - PubMed
    1. Akdis D, Saguner AM, Shah K, Wei C, Medeiros-Domingo A, von Eckardstein A, Lüscher TF, Brunckhorst C, Chen HSV, Duru F. (2017) Sex hormones affect outcome in arrhythmogenic right ventricular cardiomyopathy/dysplasia: from a stem cell derived cardiomyocyte-based model to clinical biomarkers of disease outcome. Eur Heart J 38:1498–1508. - PMC - PubMed
    1. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (2002) Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [published correction appears in JAMA (2003) 289:178; JAMA (2004) 291:2196]. JAMA 288:2981–2997. - PubMed
    1. Arcaro G, Cretti A, Balzano S, Lechi A, Muggeo M, Bonora E, Bonadonna RC. (2002) Insulin causes endothelial dysfunction in humans: sites and mechanisms. Circulation 105:576–582. - PubMed

Publication types

LinkOut - more resources

Feedback