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.
Abstract
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
Stem cell transplantation represents a promising approach to regenerative medical therapies for many disorders, including neurodegenerative, rheumatologic, digestive, orthopedic, hematologic and cardiovascular diseases. In the case of stem cell therapy for ischemic cardiomyopathy, this promise has been blunted by a lack of understanding of critical factors governing regeneration of adult human heart muscle. This review aims to (1) summarize the characteristics and types of stem cells used to treat cardiomyopathies; (2) to survey the results of clinical trials conducted with stem cells used to treat cardiomyopathies; and (3) to understand limitations of and obstacles to effective stem cell therapies for cardiomyopathies. Stem cells contribute both constitutive and paracrine functions, exemplified by their ability to replace damaged and destroyed cells and to secrete cytokines and chemokines, respectively. Cardiac regenerative capacity, while high in most fish, amphibians and newborn mammals, is extremely limited in adult mammals. Alterations in physiologic functions necessary to prevent destructive oxidation in endotherms forced a trade-off with tissue regenerative capacity in these animals. A review of 15 stem cell trials for ischemic cardiomyopathies supports conclusions based on these considerations and underscores the need to maximize stem cell delivery efficiency. Experimental approaches to achieve this objective are reviewed.
M. Klegerman· International Journal of Tra...· 0 citations
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.
Byron W H Mui, E. Neofytou, Joseph C. Wu· Cell Reports Medicine· 0 citations
Cardiovascular disease is the leading cause of death worldwide, often resulting in a myocardial
infarction (MI), which can lead to irreversible cell death and heart failure (HF). While advances in
bioengineering and regenerative medicine offer promising solutions for patients, traditional heart
transplantations are limited due to a shortage of organ donors. To address this issue, differentiating
induced pluripotent stem cells (iPSCs) into cardiomyocytes via signaling pathways can provide a patientspecific
source of functional cardiomyocytes, and as a long-term goal it may be capable of replacing
damaged myocardial tissue. This study evaluates the role of iPSCs and different biofabrication methods,
such as bioprinting, used to create ventricular constructs and cardiac patches that support injured regions
of the heart post-MI. However, for patients with HF, bioprinting a whole-heart construct is being explored
as a future objective and is necessary to restore cardiac function when cardiac patches or ventricular
constructs are not sufficient. Despite the progress made in the field, few studies have addressed the
need to improve bioprinting vascular networks, adopt appropriate bioinks, and reduce costs for iPSC
differentiation and bioprinting technologies. If successful, this work can eventually mitigate symptoms
post-MI or contribute to addressing HF solutions, offering patients a new quality of life.
N. Shenoy· American Journal of Student...· 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, Liang-Fu Xu et al.· Journal of Controlled Releas...· 0 citations
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