Heart failure (HF) is a life-threatening disorder and is treated by drug therapies and surgical interventions such as heart transplantation and left ventricular assist device (LVAD). However, these treatments can lack effectiveness in the long term and are associated with issues such as donor shortage in heart transplantation, and infection, stroke, or gastrointestinal bleeding in LVADs. Therefore, alternative therapeutic strategies are still needed. In this respect, stem cell therapy has been introduced for the treatment of HF and numerous preclinical and clinical studies are employing a range of stem cell varieties. These stem cells, such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have been shown to improve cardiac function and attenuate left ventricular remodeling. IPSCs, which have a capacity for unlimited proliferation and differentiation into cardiomyocytes, are a promising cell source for myocardial regeneration therapy. In this review, we discuss the following topics: (1) what are iPSCs; (2) the limitations and solutions for the translation of iPSC-CMs practically; and (3) the current therapeutic clinical trials.

Mitochondrial dysfunction is a key contributor to cardiac injury and heart failure, and extracellular vesicles (EVs) have emerged as promising therapeutic agents due to their ability to deliver mitochondrial-targeted cargo. This review systematically maps the evidence on how EVs modulate mitochondrial dynamics—including fusion, fission, mitophagy, and biogenesis—in regenerative cardiology. We comprehensively searched PubMed, Scopus, and Web of Science up to September 2025 for original studies. A total of 48 studies were included, with most utilizing EVs from mesenchymal stem cells, induced pluripotent stem cells, or cardiac progenitors. The review found that EV cargo influences key pathways such as DRP1 and MFN2, restores mitochondrial membrane potential, reduces ROS accumulation, and improves cardiomyocyte survival. While engineered EVs showed enhanced specificity, a lack of standardized preparation and quantitative assessment methods remains a significant challenge. We conclude that EV-mediated mitochondrial modulation is a promising strategy for cardiac repair, but the field needs harmonized protocols, deeper mechanistic understanding, and improved translational readiness to advance beyond preclinical research. The future of this research lies in integrating systems biology and precision targeting.

Heart failure (HF) is a life-threatening disorder and is treated by drug therapies and surgical interventions such as heart transplantation and left ventricular assist device (LVAD). However, these treatments can lack effectiveness in the long term and are associated with issues such as donor shortage in heart transplantation, and infection, stroke, or gastrointestinal bleeding in LVADs. Therefore, alternative therapeutic strategies are still needed. In this respect, stem cell therapy has been introduced for the treatment of HF and numerous preclinical and clinical studies using various types of stem cells, such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have been shown to improve cardiac function and attenuate left ventricular remodeling. IPSCs, which have a capacity of unlimited proliferation and differentiation to cardiomyocytes, are a promising cell source for myocardial regeneration therapy. This review discusses the current status of cardiac regenerative therapy using iPSCs.

Background: Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) hold transformative potential for cardiovascular regenerative medicine, yet their clinical application is hindered by suboptimal mitochondrial maturation and metabolic inefficiencies. This systematic review evaluates targeted strategies for optimizing mitochondrial function, integrating metabolic preconditioning, substrate selection, and pathway modulation to enhance energy production and cellular resilience. Additionally, we examine the role of extracellular matrix stiffness and mechanical stimulation in mitochondrial adaptation, given their influence on metabolism and maturation. Methods: A comprehensive analysis of recent advancements in iPSC-CM maturation was conducted, focusing on metabolic interventions that enhance mitochondrial structure and function. Studies employing metabolic preconditioning, lipid and amino acid supplementation, and modulation of key signaling pathways, including PGC-1α, AMPK, and mTOR, were reviewed. Computational modeling approaches predicting optimal metabolic shifts were assessed, alongside insights into reactive oxygen species (ROS) signaling, calcium handling, and the impact of electrical pacing on energy metabolism. Results: Evidence indicates that metabolic preconditioning with fatty acids and oxidative phosphorylation enhancers improves mitochondrial architecture, cristae density, and ATP production. Substrate manipulation fosters a shift toward adult-like metabolism, while pathway modulation refines mitochondrial biogenesis. Computational models enhance precision, predicting interventions that best align iPSC-CM metabolism with native cardiomyocytes. The synergy between metabolic and biomechanical cues offers new avenues for accelerating maturation, bridging the gap between in vitro models and functional cardiac tissues. Conclusions: Strategic metabolic optimization is essential for overcoming mitochondrial immaturity in iPSC-CMs. By integrating biochemical engineering, predictive modeling, and biomechanical conditioning, a robust framework emerges for advancing iPSC-CM applications in regenerative therapy and disease modeling. These findings pave the way for more physiologically relevant cell models, addressing key translational challenges in cardiovascular medicine.

The demand for mass production of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is escalating, driven by their potential to revolutionize cardiac regenerative therapies. The development of large-scale production protocols for iPSC-CMs is crucial to attain their therapeutic potential, enabling the treatment of millions of patients’ worldwide suffering from cardiovascular diseases. However, the scalable production of iPSC-CMs hinges on overcoming several critical challenges, including cellular differentiation and maturation. In pursue of tackling these challenges, researchers are investigating novel strategies such as prolonged culture periods, mechanical stimulation, and co-culture with supporting cell types. Overcoming these challenges is essential for unlocking the full potential of iPSC-CMs and paving the way for a new era in cardiac regenerative medicine. In this review, following topics are covered: (1) improvement of differentiation and maturation of iPSC-CMs and (2) scalable production of iPSC-CMs.

Background and Objectives: Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have revolutionized cardiac research by providing patient-specific models for studying arrhythmias. However, their clinical application is hindered by arrhythmogenic risks associated with grafted iPSC-CMs. This review aims to delineate the current limitations in iPSC-CM-based arrhythmia modeling and explore emerging therapeutic strategies to mitigate these risks. Materials and Methods: A comprehensive literature review was conducted, focusing on studies published in the last two decades that address the electrophysiological characteristics of iPSC-CMs, their arrhythmogenic potential, and therapeutic interventions. Sources include peer-reviewed journals, clinical trial reports, and recent advancements in stem cell technology. Results: Findings indicate that while iPSC-CMs offer a promising platform for arrhythmia modeling, challenges such as cellular heterogeneity, immaturity, and proarrhythmic potential persist. Advancements in maturation protocols, co-culture systems, and gene editing techniques have shown promise in enhancing the safety profile of iPSC-CMs. Conclusions: Addressing the arrhythmogenic risks associated with iPSC-CMs requires a multifaceted approach, including improved differentiation protocols, maturation strategies, and therapeutic interventions. Continued research is essential to translate these models into safe and effective clinical applications.