Human heart organoids: current applications and future perspectives

Abstract

Cardiovascular disease (CVD) stands as the leading cause of death globally, causing 18 million deaths per year annually.1 Conventionally, animal and cellular models have been extensively used to investigate mechanisms of CVD, establish cardiac safety, and develop new therapies. Nonetheless, ∼90% of drugs developed in animal models fail in clinical trials, ∼45% due to unanticipated human toxicity, particularly cardiotoxicity. The limitations of current models highlight the urgent need for more sophisticated tools to investigate human diseases and accelerate the translation of research from bench to bedside. Over the last decade, and owing to significant advances in stem cell technologies, organoids have emerged as powerful tools in this respect. Organoids are three-dimensional, miniature organ-like structures that mimic the architecture and function of real organs, providing a more physiologically relevant model for research compared with traditional two-dimensional cell cultures. Efforts to create human heart organoids (hHOs) date back to the mid-2010s, but only recently have significantly faithful models been achieved.2,3 The delay, compared with other organoid types, can be attributed to the unique challenges posed by cardiac tissue, such as anatomical complexity and biomechanics. However, in 2021 this barrier was surpassed, and we saw the emergence, in a short period of time, of several protocols to generate advanced hHOs from human pluripotent stem cells (PSCs).4,5 Combining developmental biology and bioengineering, these organoids emphasized the self-organizing capability of PSCs. By mimicking key stages of embryonic development, hHOs were guided to form atrial and ventricular cardiomyocytes, first and second heart fields, epicardial and endocardial cells, cardiac fibroblasts, endothelial cells, and distinct cardiac chambers.4,5 Furthermore, these organoids were highly functional in electrophysiological and metabolic terms and were successfully employed to model congenital heart disease (CHD) due to genetic defects as well as maternal and environmental conditions (e.g. diabetes during gestation).4,5 Human heart organoids offer groundbreaking potential in investigating CVD and cardiac pharmacology. They allow for the precise and unrestricted study of early disease progression in a human setting and allow us to bypass any potential ethical limitations to work with disease-relevant material from humans since patient-specific induced PSCs (iPSCs) can be obtained from a blood sample. These are important features to drive human-centric mechanistic studies and precision and personalized medicine approaches. Unlimited amounts of organoids can be generated in a scalable fashion, with high reproducibility in recent protocols, enabling big pharma compound discovery screenings and safety testing. Another positive side effect of the adoption of this technology is reduced reliance on animal models. Figure 1 summarizes current and future applications of hHO technologies. Applications and future promises of human heart organoids for cardiovascular research. Created with BioRender.com By mimicking the early stages of heart development, hHOs can advance our understanding of the effects of teratogens, environmental factors such as diet, and genetic mutations. Additionally, organoids can be used to interrogate the safety of pregnancy-approved drugs taken by mothers during gestation and evaluate the effects of these drugs on cardiac development, addressing urgent clinical questions about drug safety during pregnancy and new origins of CHD6—a significant problem as most of CHD is assumed not to be from genetic origins. Managing a mother’s pre-existing conditions (e.g. depressive disorders) during pregnancy remains challenging since untreated conditions can affect maternal health negatively, while treatment with the required drugs may significantly increase the incidence of CHD in the foetus. In this context, hHOs present an unprecedented opportunity to reveal the connection between medications taken by the mother and adverse effects on embryonic cardiac development, contributing to prevention but also potentially illuminating alternatives. Human heart organoids provide an accurate, robust, human-relevant platform for drug discovery and cardiotoxicity testing. The main advantages of organoids are reproducibility and scalability, allowing the quick generation of thousands of human-relevant organoids enabling high-throughput screening of large libraries of compounds prior to clinical trials. It is remarkable that this can be done at possibly reduced cost and shortened time than in animal studies. Human heart organoids also have emulated the human heart’s electrophysiological complexity much better than animal models or cellular models currently in use and can radically improve the prediction of arrhythmogenic risk. In drug discovery, hHOs can be used to carry out precise compound screenings for therapeutic discovery. These applications are already possible with existing tools, and we and other groups have started screening efforts to this end.7 Human heart organoids offer a sophisticated platform for disease modelling, particularly in the context of CHD. With relevant cellular complexity, morphology, and electrophysiological properties mirroring the human heart, organoids enable detailed modelling of CHD. This includes scenarios such as ventricular septal defects arising from maternal conditions like pre-gestational diabetes, obesity, or infections during pregnancy.7 While challenges arise in modelling adult CVD, recent advances in maturation protocols for cardiomyocytes suggest attainable progress.8 Implementation of organ-on-chip technologies may further enhance organoid maturity, facilitating modelling of CVDs associated with abnormal blood flow. The integration of hHOs with -omics technologies and co-culture with organoids representing other physiological systems accelerates innovation, offering a multi-organoid approach to comprehend organ interactions under disease conditions and drug exposure. This holds promise for advancing stagnant areas in cardiac research, such as understanding atrial fibrillation mechanisms and treatment. The integration of precision medicine, artificial intelligence (AI), and digital twin technologies promises a revolution in personalized healthcare, tailoring treatments to individual characteristics.9 Human heart organoids, with their low-cost and scalable modelling of patient hearts, present an opportunity for large data sets feeding into AI models. This could provide predictive capabilities, optimizing treatment and minimizing suffering. Human heart organoids may also aid in identifying early-stage disease markers in bodily fluids, improving diagnostics for heart diseases and other cardiovascular conditions. This convergence offers a pathway to more precise, efficient, and tailored healthcare, leveraging advanced technologies for the benefit of individual and collective well-being. As a tool for regenerative medicine, hHOs can potentially be engineered to generate specific cardiac cell types instructed in a physiological-like microenvironment, possibly offering higher quality cells, within a scalable setting, for cellular therapies aimed at treating myocardial infarction and heart failure. Advances in bioprinting and tissue engineering technologies in combination with hHOs might offer unique advantages for the construction of scaffolded cardiac tissues, marking a significant step forward towards fabricating artificial hearts for tissue repair and replacement. Finally, the use of hHOs provides an alternative to traditional animal models for studying heart-related diseases and drug responses. This may contribute to ethical considerations in research, help bridge the gap between pre-clinical studies and human clinical trials, and significantly reduce research costs. Despite these advances, work still needs to be done to improve these models. Human heart organoids lack important aspects of the heart, including absence of perfused vascularization, valves, or outflow tract. Although chambers are formed, left–right asymmetry, conductance properties, and chamber formation are poorly defined, albeit they seem to be present to some extent. Other important cell populations are absent, such as immune resident cells and neural crest contributions to innervation. Thus, increasing complexity and method reproducibility are critical tasks in the near horizon10. More importantly perhaps, current models only accurately reflect the embryonic or foetal heart but lack fidelity when compared with the adult human heart. An additional limitation frequently overlooked is the lack of technologies well-suited for the analysis of these relatively large constructs. Significant research efforts are taking place on all these fronts. All authors declare no disclosure of interest for this contribution.

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