Recent Advances of Pluripotent Stem Cell-Derived Cardiomyocytes for Regenerative Medicine

Abstract

Cardiac muscle has limited proliferative potential; therefore, loss of cardiomyocytes is irreversible and can cause or exacerbate heart failure. Although both pharmacological and non-pharmacological therapies are available, these interventions act primarily on surviving myocardium to manage symptoms and reduce-rather than reverse-adverse remodeling. The only curative option for end-stage heart failure remains heart transplantation; however, its clinical use is severely constrained by the shortage of donor organs. Consequently, regenerative therapies have gained increasing attention as potential novel treatments. Among these, cardiomyocytes derived from patient-specific pluripotent stem cells (PSCs) represent a particularly promising experimental platform for cardiac regeneration. To evaluate the potential of PSCs for cardiac repair through both in vivo and in vitro approaches, we (1) examined the hallmarks of cardiomyocyte maturation and the regulatory systems that coordinate these processes, (2) reviewed recent advances in maturation protocols and derivation techniques, (3) discussed how the cellular microenvironment enhances maturation and function, and (4) identified current barriers to clinical translation. Importantly, we integrated developmental biology with protocol design to provide a mechanistic foundation for PSC-based regeneration. Specifically, insights from cardiac development-such as signaling pathways governing proliferation, alignment, and excitation-contraction coupling-were explicitly linked to the refinement of PSC differentiation and maturation protocols. This developmental perspective allows us to bridge pathology and stem-cell methodology, explaining how disruptions in native cardiac maturation can inform strategies to produce functionally mature PSC-derived cardiomyocytes. Finally, we assessed the clinical prospects of PSC-derived cardiomyocytes, highlighting both the most recent advances and the persistent translational challenges that must be addressed before widespread therapeutic use.

Keywords: cardiac regeneration; cardiomyocyte maturation; cardiovascular disease; cell therapy; heart failure; induced pluripotent stem cells; pluripotent stem cells; tissue engineering.

Figure 1

Some of the processes, challenges, and outcomes associated with iPSC cardiomyocyte transplantation. Legend: Left Panel, The derivation of cardiomyocytes from iPSCs. iPSCs are first differentiated into cardiomyocytes with spontaneous contractile activity. These cardiomyocytes are then transplanted into the patient’s heart. Right Panel (A) Immune Rejection: Transplanted cardiomyocytes encounter immune rejection, which involves various immune cells, including neutrophils, eosinophils, basophils, and monocytes. These immune cells release cytokines, leading to the targeted destruction of the transplanted cells labeled as “immune-rejected cardiomyocyte.” (B) Fibrosis Formation: After immune rejection, inflammatory cytokines like TNF-α and TGF-β promote the activation of myofibroblasts. Myofibroblasts synthesize ECM proteins, resulting in scar tissue formation and fibrosis, which impairs cardiac function. (C) Post-Transplant Arrhythmias: Imperfect electrical coupling between native and transplanted cardiomyocytes leads to arrhythmias. The asynchronous electrical signals between native and transplanted cells create electrical instability, causing post-transplant arrhythmias. (D) Loss of Automaticity and Cell Death: Some transplanted cells initially display active automaticity, generating Ca²⁺ and Na⁺ currents. However, ongoing immune response from T and B cells can cause a loss of automaticity and eventual cell death, reducing the therapeutic efficacy of the transplantation.