Proliferation and Maturation of Cardiomyocytes in the Human Heart

Heart failure is one of the leading causes of death worldwide, with mortality rates worse than many malignancies.

The pathophysiological basis of heart failure lies in the limited capacity of the heart to replace dead or dysfunctional myocardium.

We have demonstrated that the generation of new cardiomyocytes in humans is not restricted to early development but continues throughout life.

However, cardiomyocyte proliferation is limited by cardiomyocyte maturation occurring already during the neonatal period.

If cardiomyocyte maturation-related cellular and molecular mechanisms were characterized, it could be possible to augment cardiomyocyte replacement during the treatment of cardiac disease.

Thus, this proposal seeks to explore mechanisms that underlie cardiac proliferation and maturation by identifying novel master transcriptional regulators and regulatory networks in human cardiomyocytes.

Additionally, we aim to identify microenvironmental cues enabling cardiomyocyte proliferation by transcriptional profiling of human heart organoids.

Using retrospective birth dating we will study whether cardiomyocyte renewal in young and old diseased human hearts is differentially regulated and whether young hearts with a diploid ploidy profile have a higher capacity to regenerate.

Given success the proposed studies will expand our understanding of the different aspects of myocardial renewal and bring us closer to the development of new treatments for heart disease.