2026· American Journal of Student Research· 0 citations
TL;DR
Successfully overcoming translational barriers will require standardized trial designs, rigorous product characterization criteria, and greater emphasis on clinically meaningful endpoints.
Abstract
Heart failure following a myocardial infarction (MI) remains a major global health challenge. This
is largely attributable to the adult human heart’s limited innate regenerative capacity, which results in
ventricular fibrosis, remodeling, and the formation of scar tissue. Early clinical trials evaluating bone
marrow-derived mononuclear cells (BMMNCs) and mesenchymal stromal cells (MSCs) demonstrated
acceptable safety profiles. Still, they produced only modest improvements in cardiac function and failed
to replicate the robust benefits observed in preclinical models. This review examines the biological
and methodological barriers responsible for this translational gap. Biologically, therapeutic efficacy is
limited by the hostile post-infarction environment, which is characterized by hypoxia, inflammation, and
oxidative stress, all of which contribute to extensive donor cell death, poor cell retention, and inadequate
electrical integration with host myocardium. Methodologically, progress is hindered by small clinical
trial sizes with limited statistical power coupled with high heterogeneity in cell preparations, dosing, and
delivery routes. Furthermore, the widespread reliance on surrogate imaging endpoints, particularly on
the left ventricular ejection fraction (LVEF), rather than definitive clinical outcomes, such as mortality,
heart-failure hospitalization, functional status, and quality of life, limits the interpretation of therapeutic
efficacy. In response to these limitations, the field is shifting toward cell-free therapies utilizing
extracellular vesicles and exosomes to deliver cardiovascular bioactive molecules, as well as direct
cardiac reprogramming to convert resident scar-forming fibroblasts into functional cardiomyocytes.
Successfully overcoming these translational barriers will require standardized trial designs, rigorous
product characterization criteria, and greater emphasis on clinically meaningful endpoints.
Myocardial infarction, characterized by irreversible cardiomyocyte loss, progressive cardiac fibrosis and subsequent deteriorated heart function, constitute an intractable global health burden. Promoting endogenous cardiomyocyte proliferation to achieve functional cardiac regeneration represents an available foreground for combatting heart failure. Based on extensive preclinical evidence, researchers have characterized the cellular and molecular mechanisms governing cardiomyocyte proliferation and elucidated the modulatory influence of the metabolic factors and extracellular matrix. Insights from various studies have facilitated the development of regenerative approaches that reprogramming terminally differentiated cardiomyocytes toward a more metabolic plastic and fetal-like state, thereby enhancing the proliferative and reparative potential. Integration of metabolic and mechanical signals has emerged as a critical determinant of successful cardiomyocyte reactivation, providing a mechanistic rationale for combinatorial therapeutic strategies. Nevertheless, despite remarkable progression in mechanistic understanding and proof-of-concept studies, cardiac regeneration protocols advanced to robust clinical validation or pharmacal application have yet to be developed. This review provides a historical and biologically grounded synthesis of preclinical advances in cardiac repair, regeneration and cardiomyocyte reprogramming, with particular emphasis on translational feasibility and clinical applicability. Current strategies and preclinical trial outcomes are summarized to construct a readiness framework that maps the developmental maturity of each approach. Finally, the review highlights existing biological and technical barriers, as well as emerging opportunities poised to shape the future of cardiac regenerative medicine.
Yilong Li, Kexiao Zheng, Yinghua Liu et al.· Molecular Biomedicine· 0 citations
This review systematically analyzes the key issues facing EV-based therapeutic strategies in their progression from experimental research to clinical application, providing a practical theoretical framework for EV-based myocardial repair therapies and clarifying the prospects for EVs in the treatment of MI.
Kaiyi Zhu, Jing Bai, Liangfu Xu et al.· Journal of Controlled Releas...· 0 citations
Simple Summary Cardiovascular diseases are the leading cause of death worldwide, accounting for 19.2 million deaths in 2023. When a heart attack occurs, the affected cardiomyocytes die rapidly, and the adult heart replaces them at only about 1% per year, far too slowly to compensate for the loss following a large infarction. Current treatments stabilise patients but cannot rebuild lost muscle. Over the past two decades, clinical trials have tested stem cells from bone marrow, fat tissue, umbilical cord blood, and reprogrammed adult cells. These approaches are consistently safe. Some have produced modest improvements in cardiac function and scar reduction, but the transplanted cells rarely persist long enough to form new heart muscle. The benefit they confer appears to arise mainly from signalling particles they release called extracellular vesicles and exosomes, which carry microRNAs and proteins that reduce scarring, stimulate blood vessel growth, and dampen post-injury inflammation. This finding has opened a new research direction: engineering those particles directly, without transplanting cells at all. 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 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
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.
Byron W H Mui, E. Neofytou, Joseph C. Wu· Cell Reports Medicine· 0 citations
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