Abstract:
Background. Ischemic heart disease remains a leading cause of mortality worldwide. The application
of heart transplantation is limited by donor shortage and risk of rejection. Therefore, cardiac tissue
engineering has emerged as a promising regenerative approach to restore myocardial function.
However, most engineered constructs exhibit immature, fetal-like cardiomyocyte phenotypes
characterized by reduced conduction velocity, weak contractile force, altered gene expression, and
unstable resting membrane potential.
Objective of the Study. To analyze and systematize current strategies for promoting maturation of
stem cell-derived cardiomyocytes, including long-term culture, biophysical stimulation, metabolic
interventions, and in-vivo studies.
Material and Methods. The study presented here is based on specialized literature extracted from
databases such as PubMed, HINARI, and ScienceDirect. The search covered 18 publications from
2020 to 2025.
Results. Cardiomyocyte maturation encompasses several key processes, including cell size increase,
myofibril maturation, metabolic transition from glycolysis to fatty acid oxidation, formation of a
mature action potential, T-tubule development, mitochondrial expansion, and polyploidization.
Biophysical stimulation, such as electrical pacing, cyclic mechanical stretch, substrate stiffness (8-11
kPa), and nanotopography, plays a central role in maturation. In contrast, the absence of mechanical
stress leads to sarcomere disassembly and reduced contractility. Long-term culture improves cell
morphology and function, but has proven insufficient for T-tubule formation. Co-culture with
endothelial cells, epicardial cells, and cardiac fibroblasts enhances vascularization, graft size, and
structural organization. The optimal fibroblast content in the seed (30%) promotes cardiomyocyte
proliferation by secreting extracellular matrix factors, while adult fibroblasts secrete growth cytokines.
Metabolic modulation promotes fatty acid oxidation and mitochondrial biogenesis by using T3,
glucocorticoids, angiotensin II, and endothelial-derived microRNAs. In vivo transplantation appears
to be the most effective method, as numerous experiments have demonstrated the transition of
cardiomyocytes to mature isoforms. This demonstrates that the cells have the potential for maturation,
but in vitro conditions are inadequate.
Conclusion. Overall, even with these modern natural engineering techniques, stem cell-derived
cardiomyocytes in artificial cardiac tissue remain primarily in the early and late fetal stages of
cardiomyocyte maturity. Although it possesses regenerative potential, incomplete maturation remains
a significant barrier to clinical translation.
