Naturally Engineered Maturation of Cardiomyocytes

Area of Science:

• Cardiovascular Research
• Regenerative Medicine
• Stem Cell Biology

Background:

• Ischemic heart disease is a leading cause of death, with heart transplantation facing limitations like donor scarcity and rejection.
• Human pluripotent stem cell-derived cardiomyocytes offer a potential alternative but exhibit immature, fetal-like phenotypes in engineered tissues.
• A significant gap exists between the functionality of engineered cardiac tissue and native adult myocardium.

Purpose of the Study:

• To review natural developmental mechanisms of cardiomyocyte maturation.
• To discuss *in vitro* strategies for improving cardiomyocyte maturation through natural engineering.
• To highlight the role of electrical/mechanical stimulation, extracellular matrix, and non-cardiomyocyte interactions in maturation.

Main Methods:

• Integration of natural cardiomyocyte developmental mechanisms.
• Discussion of *in vitro* natural engineering approaches mimicking development.
• Analysis of synergistic factors influencing cardiomyocyte maturation.

Main Results:

• Current natural engineering approaches yield cardiomyocytes in early to late fetal stages of maturity within engineered heart tissue.
• Despite advancements, a significant functionality gap persists between engineered and native adult cardiac tissue.
• Elucidating the *in vivo* fetal microenvironment's role in cardiomyocyte maturation is crucial.

Conclusions:

• Pluripotent stem cell-derived cardiomyocytes in engineered heart tissue require further maturation to reach adult phenotypes.
• Developing natural engineering strategies that emulate the fetal microenvironment is essential for clinical relevance.
• Future research should focus on understanding *in vivo* developmental cues to advance cardiac regeneration.