Mechanisms in cardiac development and regeneration

BackgroundDue to a very limited regenerative capacity of the adult mammalian heart, cardiomyocyte loss in the setting of acute and chronic heart diseases is not adequately compensated by myocyte regeneration. The ensuing adverse remodelling processes and fibrosis deteriorate the heart's pumping capacity finally leading to terminal heart failure, which is associated with a poor prognosis. Due to a lack of ultimately effective treatment options, there is an urgent need for the development of alternative, especially curative treatment strategies.Objective: This study investigated the mechanisms of mesodermal differentiation during cardiac development, cardiomyocyte transdifferentiation of fibroblasts (cardiac reprogramming), and a reactivation of putative endogenous stem cells after cardiac injury events.Material and methods: Review and discussion of original research papers cumulatively awarded with the 2022 Ernst Derra Prize and a current literature search via MEDLINE and PubMed.Results: 1. The zinc finger transcription factors Ying Yang 1 (YY1) and Myeloid zinc finger 1 (Mzf1) are important modulators of mesodermal cardiomyocyte differentiation.2. The forced overexpression of cardiac transcription factors results in only partial cardiomyocyte reprogramming of fibroblasts.3. In the adult heart the plasticity of Nkx2.5CE-positive cells reactivated by cardiac injury events is fundamentally different from that observed during embryofetal cardiogenesis and the neonatal period.Conclusion: A deeper molecular understanding of the mechanisms of cardiac developmental and endogenous regenerative processes is a central goal of cardiovascular research in order to move a decisive step forward to find effective regenerative therapeutic options for the treatment of patients with advanced heart disease. Currently, tissue engineering, cellular reprogramming and endogenous stimulation of cardiomyocyte proliferation appear to be the most promising approaches.