Abstract
Ischemic heart disease is the leading cause of death worldwide. The blockade of coronary arteries limits oxygen-rich blood to the heart and consequently there is cardiomyocyte (CM) cell death, inflammation, fibrotic scarring, and myocardial remodeling. Unfortunately, current therapeutics fail to effectively replace the lost cardiomyocytes or prevent fibrotic scarring, which results in reduced cardiac function and the development of heart failure (HF) in the adult mammalian heart. In contrast, neonatal mice are capable of regenerating their hearts following injury. However, this regenerative response is restricted to the first week of post-natal development. Recently, we identified that cholinergic nerve signaling is necessary for the neonatal mouse cardiac regenerative response. This demonstrates that cholinergic nerve stimulation holds significant potential as a bioelectronic therapeutic tool for heart disease. However, the mechanisms of nerve directed regeneration in the heart remain undetermined. In this review, we will describe the historical evidence of nerve function during regeneration across species. Specifically, we will focus on the emerging role of cholinergic innervation in modulating cardiomyocyte proliferation and inflammation during heart regeneration. Understanding the role of nerves in mammalian heart regeneration and adult cardiac remodeling can provide us with innovative bioelectronic-based therapeutic approaches for treatment of human heart disease.
Highlights
In this review, our goal is to highlight the evolutionarily conserved role of nerve signaling in promoting regeneration following injury across multiple tissues and different species
Nerve-guided tissue regeneration has been demonstrated to be evolutionarily conserved across species, but we are just starting to understand the role of nerves during mammalian heart regeneration
Our goal in this review is to provide an overview of how cholinergic nerves function during heart regeneration
Summary
Our goal is to highlight the evolutionarily conserved role of nerve signaling in promoting regeneration following injury across multiple tissues and different species. We highlight the importance of cholinergic nerve signaling in regulating neonatal mouse heart regeneration, where ablation of cholinergic nerve signaling either pharmacologically or mechanically resulted in impaired cardiac regeneration and revealed a previously unappreciated role for nerves in cardiac regeneration (Fig. 1a). We discuss the intersection between cholinergic nerve signaling and the immune response during cardiac regeneration in the neonatal heart, as well as during cardiac repair and remodeling in the adult heart. We summarize the results of the VNS clinical trials to promote cardiac remodeling in adults with heart failure. These findings as well as future studies aimed at elucidating the mechanisms of cholinergic nerve stimulation of cardiomyocyte proliferation, inflammation and heart regeneration have important therapeutic potential for bioelectronic methods to stimulate adult heart repair
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