The challenge of cardiomyocyte cytokinesis

One of the major challenges in cardiac regeneration is not simply getting adult cardiomyocytes back into the cell cycle, but getting them to complete cell division. After myocardial infarction (MI), this limited ability to undergo cytokinesis remains an important barrier to replacing lost cardiomyocytes. In their recent study in Circulation, Lu and colleagues approach this problem from both sides: activating pathways that promote proliferation while simultaneously removing signals that restrain it. 

A dual-target strategy for cardiac regeneration

Using transcriptomic analyses across several models of cardiac regeneration, including dedicated systems for tracking cardiomyocyte cytokinesis, the authors identified two opposing regulators, Nfyb, which promotes proliferation, and Nr3c1, encoding the glucocorticoid receptor, which acts as a brake. Nfyb overexpression or Nr3c1 inhibition individually enhanced cardiomyocyte proliferation and improved cardiac function after MI. The most striking results, however, came from combining the two. A cardiomyocyte-targeted AAV9 system allowing inducible Nfyb expression together with CRISPR-mediated Nr3c1 deletion markedly increased the formation of new cardiomyocytes and clonal expansion after MI. This was accompanied by improved ventricular function and reduced infarct size, while the pro-proliferative effect was also demonstrated in human engineered heart tissue. 

Controlled regeneration

What makes this study particularly interesting is the idea that cardiac regeneration may require more than switching on a single proliferative pathway. Instead, effective regeneration may depend on finding the right balance between releasing endogenous restraints and providing a sufficient proliferative stimulus. Importantly, the authors also address the need for control, as prolonged Nfyb/Nr3c1 intervention resulted in cardiac hyperplasia, emphasizing that when it comes to cardiac regeneration, when and for how long proliferation is induced may be just as important as how strongly it is stimulated. 

From proof of concept to clinical translation

Translation to patients remains a considerable step, particularly given the complexity of cardiac gene delivery and genome editing. Nevertheless, this work offers an intriguing proof of concept. Rather than targeting a single pathway, carefully coordinated activation and release of proliferative brakes may provide a more effective route towards meaningful cardiac regeneration after MI.