Although cellular therapies hold great promise for the treatment of human disease, results from several initial clinical trials have not shown a level of efficacy required for their use as a first ...line therapy. Here we discuss how in vivo molecular imaging has helped identify barriers to clinical translation and potential strategies that may contribute to successful transplantation and improved outcomes, with a focus on cardiovascular and neurological diseases. We conclude with a perspective on the future role of molecular imaging in defining safety and efficacy for clinical implementation of stem cell therapies.
This Review examines how in vivo molecular imaging has helped identify barriers to clinical translation of cell therapies and highlights potential strategies that may contribute to successful transplantation and improved outcomes.
Sex differences in the development of the normal heart and the prevalence of cardiomyopathies have been reported. The molecular basis of these differences remains unclear. Sex differences in the ...human heart might be related to patterns of gene expression. Recent studies have shown that sex specific differences in gene expression in tissues including the brain, kidney, skeletal muscle, and liver. Similar data is limited for the heart. Herein we address this issue by analyzing donor and post-mortem adult human heart samples originating from 46 control individuals to study whole-genome gene expression in the human left ventricle. Using data from the genotype tissue expression (GTEx) project, we compared the transcriptome expression profiles of male and female hearts. We found that genes located on sex chromosomes were the most abundant ones among the sexually dimorphic genes. The majority of differentially expressed autosomal genes were those involved in the regulation of inflammation, which has been found to be an important contributor to left ventricular remodeling. Specifically, genes on autosomal chromosomes encoding chemokines with inflammatory functions (e.g. CCL4, CX3CL1, TNFAIP3) and a gene that regulates adhesion of immune cells to the endothelium (e.g., VCAM1) were identified with sex-specific expression levels. This study underlines the relevance of sex as an important modifier of cardiac gene expression. These results have important implications in the understanding of the differences in the physiology of the male and female heart transcriptome and how they may lead to different sex specific difference in human cardiac health and its control.
Familial hypertrophic cardiomyopathy (HCM) is a prevalent hereditary cardiac disorder linked to arrhythmia and sudden cardiac death. While the causes of HCM have been identified as genetic mutations ...in the cardiac sarcomere, the pathways by which sarcomeric mutations engender myocyte hypertrophy and electrophysiological abnormalities are not understood. To elucidate the mechanisms underlying HCM development, we generated patient-specific induced pluripotent stem cell cardiomyocytes (iPSC-CMs) from a ten-member family cohort carrying a hereditary HCM missense mutation (Arg663His) in the MYH7 gene. Diseased iPSC-CMs recapitulated numerous aspects of the HCM phenotype including cellular enlargement and contractile arrhythmia at the single-cell level. Calcium (Ca2+) imaging indicated dysregulation of Ca2+ cycling and elevation in intracellular Ca2+ (Ca2+i) are central mechanisms for disease pathogenesis. Pharmacological restoration of Ca2+ homeostasis prevented development of hypertrophy and electrophysiological irregularities. We anticipate that these findings will help elucidate the mechanisms underlying HCM development and identify novel therapies for the disease.
► Patient-specific iPSC-CMs recapitulate the HCM phenotype at the single-cell level ► iPSC-CMs with the HCM Arg663His mutation have irregular Ca2+ handling properties ► Elevation in Ca2+i induces both hypertrophy and arrhythmia in iPSC-CMs ► Pharmacological treatment of Ca2+ imbalance prevents HCM phenotype development
Modeling of familial hypertrophic cardiomyopathy using human iPSCs highlights a role for Ca2+ dysregulation in disease pathology.
Thrombosis has long been reported as a potentially deadly complication of respiratory viral infections and has recently received much attention during the global coronavirus disease 2019 pandemic. ...Increased risk of myocardial infarction has been reported during active infections with respiratory viruses, including influenza and severe acute respiratory syndrome coronavirus 2, which persists even after the virus has cleared. These clinical observations suggest an ongoing interaction between these respiratory viruses with the host’s coagulation and immune systems that is initiated at the time of infection but may continue long after the virus has been cleared. In this review, we discuss the epidemiology of viral-associated myocardial infarction, highlight recent clinical studies supporting a causal connection, and detail how the virus’ interaction with the host’s coagulation and immune systems can potentially mediate arterial thrombosis.
Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human ...reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression. Using multiple tissues from a single donor enabled identification of the clonal distribution of T cells between tissues, identification of the tissue-specific mutation rate in B cells, and analysis of the cell cycle state and proliferative potential of shared cell types across tissues. Cell type-specific RNA splicing was discovered and analyzed across tissues within an individual.
After the Vietnam/American War, an estimated 1-2.5 million people were imprisoned in reeducation camps or trại học tập cải tạo with no formal charges or trials and 165,000 people were estimated to ...have died in the camps either from malnourishment, disease, or execution. In this article, I analyze my father Tam Van Nguyen's oral history of reeducation camps with excerpts from the Socialist Republic of Vietnam's memorandum to Amnesty International. I do so in order to theorize states of suspension as an embodied analytic that further draws on Frantz Fanon's discussion of the importance of "knowing the strength of their own muscles" in national struggle to further push the boundaries of what freedom can feel like in the body. I locate states of suspension at the crux between three states of being: deprivation and indulgence, citizenship and criminality, and life and death, as they are enacted through the techniques of torture and punishment, performances of sovereign power, and modes of bodily capture. This research seeks to nuance Cold War dichotomies of promises of freedom by U.S. liberal war and Marxist-Leninist communist revolution to challenge our relationship to nation-state building as the ultimate achievement of national independence.
Cardiotoxicity is a leading cause for drug attrition during pharmaceutical development and has resulted in numerous preventable patient deaths. Incidents of adverse cardiac drug reactions are more ...common in patients with preexisting heart disease than the general population. Here we generated a library of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with various hereditary cardiac disorders to model differences in cardiac drug toxicity susceptibility for patients of different genetic backgrounds.
Action potential duration and drug-induced arrhythmia were measured at the single cell level in hiPSC-CMs derived from healthy subjects and patients with hereditary long QT syndrome, familial hypertrophic cardiomyopathy, and familial dilated cardiomyopathy. Disease phenotypes were verified in long QT syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy hiPSC-CMs by immunostaining and single cell patch clamp. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and the human ether-a-go-go-related gene expressing human embryonic kidney cells were used as controls. Single cell PCR confirmed expression of all cardiac ion channels in patient-specific hiPSC-CMs as well as hESC-CMs, but not in human embryonic kidney cells. Disease-specific hiPSC-CMs demonstrated increased susceptibility to known cardiotoxic drugs as measured by action potential duration and quantification of drug-induced arrhythmias such as early afterdepolarizations and delayed afterdepolarizations.
We have recapitulated drug-induced cardiotoxicity profiles for healthy subjects, long QT syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy patients at the single cell level for the first time. Our data indicate that healthy and diseased individuals exhibit different susceptibilities to cardiotoxic drugs and that use of disease-specific hiPSC-CMs may predict adverse drug responses more accurately than the standard human ether-a-go-go-related gene test or healthy control hiPSC-CM/hESC-CM screening assays.
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