MicroRNA-dependent suppression of biological pacemaker activity induced by TBX18

Sanchez, Lizbeth; Mesquita, Thássio; Zhang, Rui; Liao, Ke; Rogers, Robert W.; Lin, Yen‐Nien; Miguel-dos-Santos, Rodrigo; Akhmerov, Akbarshakh; Li, Liang; Nawaz, Asma; Holm, Kevin; Marbán, Eduardo; Cingolani, Eugenio

doi:10.1016/j.xcrm.2022.100871

Cited by 5 publications

(5 citation statements)

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“…This method unleashes the biological pacemaker activity using a virus-free delivery system. 11 Human-induced pluripotent stem cells (hiPSCs) and embryonic stem cells have also been used to generate spontaneously beating cellular clusters, demonstrating pacemaker activity after transplantation into the ventricle. [12][13][14] While the success of cell-based therapy depends on the number of engrafted cells, 13 whether the engrafted cells are electrically mature and stable remains to be determined.…”

Section: Current Biological Pacemakersmentioning

confidence: 99%

Biological Pacemakers: Present and Future

Mesquita,

Miguel-dos-Santos,

Cingolani

2024

Circulation Research

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Section: Current Biological Pacemakersmentioning

confidence: 99%

Biological Pacemakers: Present and Future

Mesquita,

Miguel-dos-Santos,

Cingolani

2024

Circulation Research

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“…237,290,309 The expression of ≥1 of these transcription factors downregulates genes specific for the working myocardium and influences genes relevant for pacemaking. [310][311][312][313][314] In view of the complexity of sinoatrial pacemaking and the differences in the various promising approaches to develop biological pacemakers, it will be interesting to see in which direction the field will progress in the future.…”

Section: Hcn Channels In Disease and Therapymentioning

confidence: 99%

Pacemaker Channels and the Chronotropic Response in Health and Disease

Hennis,

Piantoni,

Biel

et al. 2024

Circulation Research

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Loss or dysregulation of the normally precise control of heart rate via the autonomic nervous system plays a critical role during the development and progression of cardiovascular disease—including ischemic heart disease, heart failure, and arrhythmias. While the clinical significance of regulating changes in heart rate, known as the chronotropic effect, is undeniable, the mechanisms controlling these changes remain not fully understood. Heart rate acceleration and deceleration are mediated by increasing or decreasing the spontaneous firing rate of pacemaker cells in the sinoatrial node. During the transition from rest to activity, sympathetic neurons stimulate these cells by activating β-adrenergic receptors and increasing intracellular cyclic adenosine monophosphate. The same signal transduction pathway is targeted by positive chronotropic drugs such as norepinephrine and dobutamine, which are used in the treatment of cardiogenic shock and severe heart failure. The cyclic adenosine monophosphate–sensitive hyperpolarization–activated current (I f ) in pacemaker cells is passed by hyperpolarization-activated cyclic nucleotide-gated cation channels and is critical for generating the autonomous heartbeat. In addition, this current has been suggested to play a central role in the chronotropic effect. Recent studies demonstrate that cyclic adenosine monophosphate–dependent regulation of HCN4 (hyperpolarization-activated cyclic nucleotide-gated cation channel isoform 4) acts to stabilize the heart rate, particularly during rapid rate transitions induced by the autonomic nervous system. The mechanism is based on creating a balance between firing and recently discovered nonfiring pacemaker cells in the sinoatrial node. In this way, hyperpolarization-activated cyclic nucleotide-gated cation channels may protect the heart from sinoatrial node dysfunction, secondary arrhythmia of the atria, and potentially fatal tachyarrhythmia of the ventricles. Here, we review the latest findings on sinoatrial node automaticity and discuss the physiological and pathophysiological role of HCN pacemaker channels in the chronotropic response and beyond.

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“…Following these initial successes, several delivery technologies through adeno-associated virus or chemical-modified mRNAs have been developed to induce Tbx18 expression in VMs, but avoid adenoviral vector-related immunogenicity [ 57 , 58 ]. Tbx18 expression by the adeno-associated viral vector induced reprogramming and generated PCs in the in-vitro cell models [ 57 ].…”

Section: Introductionmentioning

confidence: 99%

“…RNA therapeutics should be highlighted as those comprise a rapidly expanding category of drugs for many diseases [ 59 , 60 ]. The Tbx18 mRNAs were chemically modified to avoid an immune response triggered by naked RNA [ 58 ]. However, the Tbx18 expression after the delivery of modified Tbx18 mRNAs was compromised by the activation of miR-1-3p and miR-1b.…”

Section: Introductionmentioning

confidence: 99%

“…However, the Tbx18 expression after the delivery of modified Tbx18 mRNAs was compromised by the activation of miR-1-3p and miR-1b. Therefore, the sustained Tbx18 expressions could only be reached by combining modified Tbx18 mRNAs and antagomirs of miR-1-3p and miR-1b, which induced de novo biological pacemaker activity at the injection site in rats’ hearts [ 58 ].…”

Section: Introductionmentioning

confidence: 99%

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Harnessing cell reprogramming for cardiac biological pacing

Liu,

Chen,

2023

J Biomed Sci

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Electrical impulses from cardiac pacemaker cardiomyocytes initiate cardiac contraction and blood pumping and maintain life. Abnormal electrical impulses bring patients with low heart rates to cardiac arrest. The current therapy is to implant electronic devices to generate backup electricity. However, complications inherent to electronic devices remain unbearable suffering. Therefore, cardiac biological pacing has been developed as a hardware-free alternative. The approaches to generating biological pacing have evolved recently using cell reprogramming technology to generate pacemaker cardiomyocytes in-vivo or in-vitro. Different from conventional methods by electrical re-engineering, reprogramming-based biological pacing recapitulates various phenotypes of de novo pacemaker cardiomyocytes and is more physiological, efficient, and easy for clinical implementation. This article reviews the present state of the art in reprogramming-based biological pacing. We begin with the rationale for this new approach and review its advances in creating a biological pacemaker to treat bradyarrhythmia.

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MicroRNA-dependent suppression of biological pacemaker activity induced by TBX18

Cited by 5 publications

References 50 publications

Biological Pacemakers: Present and Future

Biological Pacemakers: Present and Future

Pacemaker Channels and the Chronotropic Response in Health and Disease

Harnessing cell reprogramming for cardiac biological pacing

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