Stem Cell-Derived Cardiomyocyte Regeneration and Tissue Engineering

The field of stem cell-derived cardiomyocyte regeneration and tissue engineering seeks to overcome the limited capacity of the adult mammalian heart to self-repair by harnessing the developmental potential of pluripotent stem cells. By guiding these cells through a series of signalling cues that mimic embryonic heart formation, researchers generate cardiomyocytes that recapitulate contractile, electrophysiological and metabolic properties of native myocardium. Concurrent advances in three-dimensional culture, biomaterial scaffolds and microfluidic perfusion systems have yielded engineered heart tissues and organoid-like constructs capable of synchronous beating, force generation and vascular integration. Efforts to enhance maturation address the metabolic shift from glycolysis to fatty acid oxidation, improving structural organisation and excitation-contraction coupling. At the same time, the epicardium—once thought to play a merely protective role—is now exploited as a source of paracrine factors and multilineage progenitors that support cardiomyocyte proliferation and vascularisation. Together, these approaches aim not only to create physiologically relevant models for drug screening and disease modelling, but also to establish clinically scalable grafts for repairing injured myocardium, offering new hope for the treatment of heart failure worldwide.

Research from Nature Portfolio

Inactivation of a key mitochondrial enzyme in adult mouse cardiomyocytes has been shown to prevent the metabolic switch towards fatty acid oxidation, maintaining cells in a more plastic, less mature state. This metabolic reprogramming triggers epigenetic remodelling via accumulation of α-ketoglutarate, activation of demethylases and broad reduction of histone methylation domains governing maturation genes. The result is a resurgence of cardiomyocyte proliferation after ischaemic injury and substantive improvement in functional recovery, highlighting metabolism as a targetable barrier to heart regeneration.

A novel in vitro model of the human epicardium has been developed by coaxing pluripotent stem cells into self-organising epicardioids that exhibit retinoic acid-dependent morphogenesis and molecular patterning akin to the left ventricular wall. Single-cell transcriptomic and chromatin accessibility analyses have delineated lineage specification and differentiation trajectories, while functional assays reveal critical cross-talk between epicardial and myocardial compartments. These epicardioids faithfully recapitulate aspects of congenital hypertrophy and fibrotic remodelling, providing a versatile platform for dissecting epicardial contributions to development, disease and regenerative signalling.

Stem Cell-Derived Cardiomyocyte Regeneration and Tissue Engineering publication trend

The graph below shows the total number of articles in stem cell-derived cardiomyocyte regeneration and tissue engineering across all publications each year (not limited to Nature Index journals).

Technical terms

Pluripotent stem cell: A cell capable of differentiating into all somatic cell types, including cardiomyocytes.

Cardiomyocyte: A specialised heart muscle cell responsible for generating contractile force and electrical conduction.

Fatty acid oxidation: A metabolic pathway in mitochondria that converts fatty acids into energy, associated with cardiomyocyte maturation.

Epicardium: The outer mesothelial layer of the heart that gives rise to multiple cardiac cell lineages and secretes regenerative signals.

Tissue engineering: The practice of combining cells, scaffolds and bioactive factors to create functional tissue constructs for research or therapy.

References

1. A new paradigm for generating high-quality cardiac pacemaker cells from mouse pluripotent stem cells. Signal Transduction and Targeted Therapy (2024).
2. Inhibition of fatty acid oxidation enables heart regeneration in adult mice. Nature (2023).
3. Multi-chamber cardioids unravel human heart development and cardiac defects. Cell (2023).
4. Epicardioid single-cell genomics uncovers principles of human epicardium biology in heart development and disease. Nature Biotechnology (2023).