Regeleration is myocardium’s adaptive remodeling response to implanted biomaterial hydrogels and is a new heart failure therapy with promising success in early clinical trials.

Classified as medical devices uniquely capable of long-term myocardial engraftment, acellular hydrogel implants provide mechanical bulking and scaffolding support that can stabilize or reverse adverse remodeling like thinning. Even further, certain natural or synthetically designed hydrogels encoding specific bioactivities or signaling functions provide a promising new approach for directly regulating myocardial biology.

Here, we studied two clinically relevant hydrogels – seaweed-derived alginate (Alg) and myomatrix (MMx), extracellular matrix molecules prepared from decellularized pig heart – to gain mechanistic insight by contrasting myocardium’s molecular adaptive remodeling responses to these different biomaterials.

Alg and MMx transduced distinctive biological signals in myocardium, activating different biochemical cascades, recruiting distinctive local and circulating cells to the biomaterial-tissue interface, producing distinctive myocardial transcriptome signatures and patterns of cardiomyocyte hypertrophy, including muscle enhancer factor-2 (MEF2) activation and fetal gene program switching.

Our results reveal myocardium’s robust and highly versatile intrinsic capacity for functionally adapting to compositionally unique biomaterials. Understanding the underlying signaling networks and mechanisms will lead to optimized regeleration strategies for heart repair.