Aug 2026· Cell Reports Medicine· pp.
102962
· 0 citations· 107 references
Medicine
TL;DR
The pathophysiological rationale for cell-based therapy in heart failure with reduced ejection fraction is summarized, and the preclinical foundations of distinct hPSC-derived product formats are examined, including cell suspensions, epicardial sheets, engineered heart muscle, and cardiac spheroids, each with distinct tradeoffs and translational considerations.
Abstract
Heart failure is a major clinical and economic burden that afflicts 60 million individuals worldwide. Guideline-directed medical therapies can slow disease progression, but they cannot restore the loss of cardiomyocytes. Over the past two decades, human pluripotent stem cell (hPSC)-based technology has emerged as a leading approach to overcome limited cardiac regenerative capacity, offering a scalable source of functional human cardiomyocytes. The field is now at a pivotal translational stage, as advances in differentiation and tissue engineering have enabled hPSC-based products to enter first-in-human clinical trials. In this review, we summarize the pathophysiological rationale for cell-based therapy in heart failure with reduced ejection fraction. Then, we examine the preclinical foundations of distinct hPSC-derived product formats, including cell suspensions, epicardial sheets, engineered heart muscle, and cardiac spheroids, each with distinct tradeoffs and translational considerations. We conclude by providing updates on ongoing and recently completed clinical trials, evaluating their safety, feasibility, and preliminary efficacy outcomes.
Cardiovascular disease remains the leading cause of global mortality, in part because the heart has limited regenerative capacity. Human-induced pluripotent stem cells (hiPSCs) offer a scalable, patient-specific platform for modeling heart disease, advancing drug discovery, and developing regenerative therapies. This review evaluates recent developments in hiPSC technology, beginning with the generation of patient-specific models of inherited arrhythmias and cardiomyopathies. We examine progress in directing hiPSCs into specialized lineages, including cardiomyocytes, pacemaker cells, and Purkinje fibers, by highlighting key developmental signaling pathways and transcriptional regulators. Furthermore, we discuss emerging strategies for cell and therapeutic delivery, such as bioengineered patches and hydrogels, and address key challenges in cell maturation and functional integration. Finally, we review current clinical trials assessing the safety of hiPSC-based treatments for heart failure and conduction disorders. These advancements underscore the dual potential of hiPSCs as essential research tools and as aspirational therapeutic resources.
Berra Koskulu, Tabish Ali, Ilkin Tetik-Altintop et al.· Journal of the American Hear...· 0 citations
Oligonucleotide-based therapeutics represent a rapidly advancing class of drugs with significant potential for treating cardiovascular diseases; however, achieving efficient delivery to cardiac tissue remains a critical and unresolved challenge. A key obstacle is the limited availability of robust, physiologically relevant human in vitro models capable of supporting quantitative assessment of oligonucleotide cellular uptake and intracellular distribution. A detailed, step-by-step protocol is presented for generating self-organizing, 3D cardioids from human induced pluripotent stem cells (iPSCs) and applying them as a platform to evaluate the uptake of fluorescently labeled oligonucleotides. The protocol guides users through directed cardiac differentiation in suspension culture by temporally modulating Wnt/β-catenin signaling, enabling sequential specification of iPSCs through the mesoderm, cardiac mesoderm, and cardiomyocyte progenitor stages. Under these conditions, cells spontaneously self-assemble into beating, cavity-containing three-dimensional structures that express canonical cardiomyocyte markers. The resulting cardioids provide a scalable, experimentally tractable platform for imaging-based assessment of oligonucleotide uptake efficiency, supporting the development and optimization of delivery strategies for cardiac applications.
Ana da Rosa Soares, Marta Furtado, Rita Tomás et al.· Journal of Visualized Experi...· 0 citations
IHJ-301 significantly improved multiple parameters of cardiac function, providing preclinical evidence that IHJ-301 could offer a promising therapeutic option for DCM.
Yu Shimoyama, Kenji Kakuta, Kiho Araki et al.· Stem cell research & therape...· 0 citations
This review examines the full range of cell-based strategies studied to date, the clinical trial evidence, the barriers to progress, and what engineered vesicles, bioengineered tissue constructs, gene editing, and improved trial design might offer.
Cardiovascular disease (CVD) remains the leading cause of global mortality, yet traditional in vitro and animal models often fail to recapitulate the integrated structural, cellular, and functional complexity of the human heart. Recent advances in human pluripotent stem cell technology, developmental bioengineering, and microphysiological systems have enabled the development of diverse three-dimensional cardiac tissue models, including self-organizing cardiovascular organoids and engineered cardiac platforms, three-dimensional constructs that partially recapitulate key myocardial features. These platforms facilitate mechanistic and disease-relevant modelling of congenital and acquired cardiac disorders, allow interrogation of arrhythmogenic mechanisms, and reproduce pathophysiological processes such as ischemia–reperfusion injury, fibrotic remodelling, and inflammatory cardiomyopathy with increasing physiological relevance. In translational contexts, these models are emerging as valuable tools in drug discovery pipelines, enabling high-throughput cardiotoxicity assessment and supporting regenerative medicine strategies, thereby bridging mechanistic research with preclinical validation. Integration with cutting-edge modalities—such as single-cell and spatial multi-omics, CRISPR-based genome editing, synthetic biology circuits, and artificial intelligence-driven phenomics further enhances their maturation and predictive accuracy, although their clinical applicability remains under active investigation. Despite these advances, challenges including batch-to-batch variability, limited vascularization, metabolic immaturity, and incomplete immune system incorporation continue to constrain physiological fidelity. Additionally, ethical and regulatory considerations spanning donor consent, genetic data privacy, biobanking governance, and model-specific translational and societal implications remain critical for responsible innovation. This review presents a comprehensive synthesis of current cardiovascular organoid research, highlights emerging biomedical applications, and provides a critical perspective on the ethical frameworks essential for advancing the field responsibly.
Koushik Sen, Suravi Majumder, Dragana Stanišić et al.· American Heart Journal Plus:...· 0 citations
