Heart neurons use clock genes to control myocyte proliferation

Tampakakis, Emmanouil; Gangrade, Harshi; Glavaris, Stephanie; Htet, Myo; Murphy, Sheldon D.; Lin, Brian L.; Liu, Ting; Saberi, Amir; Miyamoto, Matthew; Kowalski, William J.; Mukouyama, Yoh-suke; Lee, Gabsang; Minichiello, Liliana; Kwon, Chulan

doi:10.1126/sciadv.abh4181

Cited by 18 publications

(17 citation statements)

References 75 publications

(121 reference statements)

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“…Neural connections are established during late embryonic and early postnatal development by a co-maturation system 10, 11 where innervation patterning and maturation relies on signals from a variety of cardiac tissues 12, 13 . Interestingly, sympathetic nerves have been demonstrated to mediate the postnatal transition of cardiomyocytes from hyperplasia to hypertrophy 14 and cardiomyocyte size 15 .…”

Section: Introductionmentioning

confidence: 99%

Defining Cardiac Nerve Architecture During Development, Disease, and Regeneration

Salamon

Halbe

Kasberg

et al. 2023

Preprint

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Cardiac nerves regulate neonatal mouse heart regeneration and are susceptible to pathological remodeling following adult injury. Understanding cardiac nerve remodeling can lead to new strategies to promote cardiac repair. Our current understanding of cardiac nerve architecture has been limited to two-dimensional analysis. Here, we use genetic models, whole-mount imaging, and three-dimensional modeling tools to define cardiac nerve architecture and neurovascular association during development, disease, and regeneration. Our results demonstrate that cardiac nerves sequentially associate with coronary veins and arteries during development. Remarkably, our results reveal that parasympathetic nerves densely innervate the ventricles. Furthermore, parasympathetic and sympathetic nerves develop synchronously and are intertwined throughout the ventricles. Importantly, the regenerating myocardium reestablishes physiological innervation, in stark contrast to the non-regenerating heart. Mechanistically, reinnervation during regeneration is dependent on collateral artery formation. Our results reveal how defining cardiac nerve remodeling during homeostasis, disease, and regeneration can identify new therapies for cardiac disease.

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Section: Introductionmentioning

confidence: 99%

Defining Cardiac Nerve Architecture During Development, Disease, and Regeneration

Salamon

Halbe

Kasberg

et al. 2023

Preprint

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“…This is nicely illustrated in a recent study, which demonstrated sympathetic neurons can influence heart development via clock genes to regulate myocyte proliferation. Here, Tampakakis et al (2021) inhibited NGF in vascular smooth cells, which resulted in impaired sympathetic innervation in the heart and reduced norepinephrine release. Interestingly, this was associated with proliferating cardiac myocytes and enlarged hearts that was directly related to downregulation in clock genes ( Per1/Per2 ).…”

Section: Discussionmentioning

confidence: 97%

Healthy cardiac myocytes can decrease sympathetic hyperexcitability in the early stages of hypertension

Davis

Liu

et al. 2022

Front. Synaptic Neurosci.

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Sympathetic neurons are powerful drivers of cardiac excitability. In the early stages of hypertension, sympathetic hyperactivity is underpinned by down regulation of M current and increased activity of Cav2.2 that is associated with greater intracellular calcium transients and enhanced neurotransmission. Emerging evidence suggests that retrograde signaling from the myocyte itself can modulate synaptic plasticity. Here we tested the hypothesis that cross culturing healthy myocytes onto diseased stellate neurons could influence sympathetic excitability. We employed neuronal mono-cultures, co-cultures of neonatal ventricular myocytes and sympathetic stellate neurons, and mono-cultures of sympathetic neurons with media conditioned by myocytes from normal (Wistar) and pre-hypertensive (SHR) rats, which have heightened sympathetic responsiveness. Neuronal firing properties were measured by current-clamp as a proxy for neuronal excitability. SHR neurons had a maximum higher firing rate, and reduced rheobase compared to Wistar neurons. There was no difference in firing rate or other biophysical properties in Wistar neurons when they were co-cultured with healthy myocytes. However, the firing rate decreased, phenocopying the Wistar response when either healthy myocytes or media in which healthy myocytes were grown was cross-cultured with SHR neurons. This supports the idea of a paracrine signaling pathway from the healthy myocyte to the diseased neuron, which can act as a modulator of sympathetic excitability.

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“…For example, it has been shown that the circadian clockwork can control cell-division cycles in the liver directly, 31 and in the heart, it has been shown that cardiac neurons use clock genes to control myocyte proliferation. 32 One limitation of our study is that the bulk RNA sequencing used allows limited insight into the transcriptome of single cells, even less into differentially expressed genes in rare cells. However, our study suggests that changes to the cardiac environment, for example, improved circadian entrainment attributable to exercise or exercise-induced cardiac cell cycle activity, might help to facilitate cytokinesis in a few cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

Restoration of Cardiomyogenesis in Aged Mouse Hearts by Voluntary Exercise

et al. 2022

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Background: The human heart has limited capacity to generate new cardiomyocytes and this capacity declines with age. Because loss of cardiomyocytes may contribute to heart failure, it is crucial to explore stimuli of endogenous cardiac regeneration to favorably shift the balance between loss of cardiomyocytes and the birth of new cardiomyocytes in the aged heart. We have previously shown that cardiomyogenesis can be activated by exercise in the young adult mouse heart. Whether exercise also induces cardiomyogenesis in aged hearts, however, is still unknown. Here, we aim to investigate the effect of exercise on the generation of new cardiomyocytes in the aged heart. Methods: Aged (20-month-old) mice were subjected to an 8-week voluntary running protocol, and age-matched sedentary animals served as controls. Cardiomyogenesis in aged hearts was assessed on the basis of 15 N-thymidine incorporation and multi-isotope imaging mass spectrometry. We analyzed 1793 cardiomyocytes from 5 aged sedentary mice and compared these with 2002 cardiomyocytes from 5 aged exercised mice, followed by advanced histology and imaging to account for ploidy and nucleation status of the cell. RNA sequencing and subsequent bioinformatic analyses were performed to investigate transcriptional changes induced by exercise specifically in aged hearts in comparison with young hearts. Results: Cardiomyogenesis was observed at a significantly higher frequency in exercised compared with sedentary aged hearts on the basis of the detection of mononucleated/diploid 15 N-thymidine–labeled cardiomyocytes. No mononucleated/diploid 15 N-thymidine–labeled cardiomyocyte was detected in sedentary aged mice. The annual rate of mononucleated/diploid 15 N-thymidine–labeled cardiomyocytes in aged exercised mice was 2.3% per year. This compares with our previously reported annual rate of 7.5% in young exercised mice and 1.63% in young sedentary mice. Transcriptional profiling of young and aged exercised murine hearts and their sedentary controls revealed that exercise induces pathways related to circadian rhythm, irrespective of age. One known oscillating transcript, however, that was exclusively upregulated in aged exercised hearts, was isoform 1.4 of regulator of calcineurin, whose regulation and functional role were explored further. Conclusions: Our data demonstrate that voluntary running in part restores cardiomyogenesis in aged mice and suggest that pathways associated with circadian rhythm may play a role in physiologically stimulated cardiomyogenesis.

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Heart neurons use clock genes to control myocyte proliferation

Abstract: Neurons regulate cardiomyocyte proliferation through clock genes.

Cited by 18 publications

References 75 publications

Defining Cardiac Nerve Architecture During Development, Disease, and Regeneration

Defining Cardiac Nerve Architecture During Development, Disease, and Regeneration

Healthy cardiac myocytes can decrease sympathetic hyperexcitability in the early stages of hypertension

Restoration of Cardiomyogenesis in Aged Mouse Hearts by Voluntary Exercise

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