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A recent study involving the Minichiello group and international collaborators, principally at the Johns Hopkins University, Baltimore, USA, and the National Institutes of Health, Bethesda, USA, has uncovered an unknown link between cardiac neurons and clock genes in the regulation of heart size and cardiomyocyte proliferation. The lack of appropriate animal models has impaired addressing the precise effect of sympathetic neurons on heart development. The authors have used a novel mouse model based on the deletion of nerve growth factor (NGF) in smooth muscle cells disrupting cardiac sympathetic innervation to demonstrate that sympathetic innervation decreases cardiomyocyte proliferation through clock genes. These novel findings suggest neuronal modulation as a therapeutic strategy for cardiac regeneration.

© Image credit: Cassie H Kwon

Sympathetic neurons (SNs) are key modulators of organ function and disease. They control heart rate, conduction velocity, contractility, and myocardial relaxation in the heart. Abnormal regulation of SNs often leads to arrhythmias, myocardial dysfunction and sudden cardiac death in adults. However, it remains unclear if SN innervation influences heart development. In a study just published in Science Advances, investigators genetically inhibited the expression of nerve growth factor (NGF) expression in smooth muscle cells in vivo and examined postnatal heart development and function.

Manipulation of NGF disrupted cardiac sympathetic innervation and profoundly decreased norepinephrine production. Furthermore, it resulted in enlarged hearts with a higher percentage of proliferating cardiomyocytes.

Transcriptomic analysis revealed upregulation of mitotic/cell cycle genes and significant downregulation of genes involved in circadian rhythm such as Period1/Period2 (Per1/Per2). Intriguingly, the proliferative phenotype of hearts with disrupted sympathetic innervation was recapitulated when the clock genes Per1/Per2 were deleted.

Investigators also found that SNs can regulate Per1/Per2 through secretion of the neurotransmitter norepinephrine. In addition, Wee1 kinase, a mitosis inhibitor, is suppressed in both SN-deficient and Per1/Per1-deleted hearts, which can induce increased mitosis entry. This study provides new mechanistic insights into nerve-mediated regulation of heart development and suggests neuronal modulation as a therapeutic strategy for cardiac regeneration

Heart neurons use clock genes to control myocyte proliferation. Tampakakis E, Gangrade H, Glavaris S, Htet M, Murphy S, Lin BL, Liu T, Saberi A, Miyamoto M, Kowalski W, Mukouyama YS, Lee G, Minichiello L, Kwon C.

Sci Adv. 2021 Dec 3;7(49):eabh4181. doi: 10.1126/sciadv.abh4181