Functional biological pacemaker generation by T-Box18 protein expression via stem cell and viral delivery approaches in a murine model of complete heart block

Gorabi, Armita Mahdavi; Hajighasemi, Saeideh; Khori, Vahid; Soleimani, Masoud; Rajaei, Maryam; Rabbani, Shahram; Atashi, Amir; Ghiaseddin, Ali; Saeid, Ali Kazemi; Tafti, Hossein Ahmadi; Sahebkar, Amirhossein

doi:10.1016/j.phrs.2019.01.034

Cited by 20 publications

(21 citation statements)

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“…These non-pacemaker cells include native CMs, such as ventricular [11,[20][21][22], atrial [23] or bundle branch myocytes [24]. They can also be stem cells, such as embryonic stem cells [25][26][27], bone marrow stem cells [13,28,29], adipose-derived stem cells [30][31][32], or induced pluripotent stem cell [14,33,34].…”

Section: Introductionmentioning

confidence: 99%

Reciprocal interaction between IK1 and If in biological pacemakers: A simulation study

Wang

et al. 2021

PLoS Comput Biol

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Pacemaking dysfunction (PD) may result in heart rhythm disorders, syncope or even death. Current treatment of PD using implanted electronic pacemaker has some limitations, such as finite battery life and the risk of repeated surgery. As such, the biological pacemaker has been proposed as a potential alternative to the electronic pacemaker for PD treatment. Experimentally and computationally, it has been shown that bio-engineered pacemaker cells can be generated from non-rhythmic ventricular myocytes (VMs) by knocking out genes related to the inward rectifier potassium channel current (IK1) or by overexpressing hyperpolarization-activated cyclic nucleotide gated channel genes responsible for the “funny” current (If). However, it is unclear if a bio-engineered pacemaker based on the modification of IK1- and If-related channels simultaneously would enhance the ability and stability of bio-engineered pacemaking action potentials. In this study, the possible mechanism (s) responsible for VMs to generate spontaneous pacemaking activity by regulating IK1 and If density were investigated by a computational approach. Our results showed that there was a reciprocal interaction between IK1 and If in ventricular pacemaker model. The effect of IK1 depression on generating ventricular pacemaker was mono-phasic while that of If augmentation was bi-phasic. A moderate increase of If promoted pacemaking activity but excessive increase of If resulted in a slowdown in the pacemaking rate and even an unstable pacemaking state. The dedicated interplay between IK1 and If in generating stable pacemaking and dysrhythmias was evaluated. Finally, a theoretical analysis in the IK1/If parameter space for generating pacemaking action potentials in different states was provided. In conclusion, to the best of our knowledge, this study provides a wide theoretical insight into understandings for generating stable and robust pacemaker cells from non-pacemaking VMs by the interplay of IK1 and If, which may be helpful in designing engineered biological pacemakers for application purposes.

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Section: Introductionmentioning

confidence: 99%

Reciprocal interaction between IK1 and If in biological pacemakers: A simulation study

Wang

et al. 2021

PLoS Comput Biol

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“…electrophysiological data have shown that iK1 can promote an increase in MdP hyperpolarization, accelerate the four-phase depolarization slope and shorten the aPd, thus increasing the frequency of i(f)-induced automaticity (18). other studies indicated that biological pacemaker activity can also be successfully created by overexpression of T-box18 (TBX18) in vivo (22)(23)(24). The hypothesized mechanisms underlying this phenomenon are as follows: i) TBX18 can convert ventricular myocytes into sinoatrial node-like cells; and ii) TBX18 drives upregulation of Hcn4 or Hcn2, and downregulation of connexin 43, which increases automaticity and the conduction of impulse.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the medium‑conductance calcium‑activated potassium channel (SK4) and the HCN2 channel to generate a biological pacemaker

et al. 2019

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ion channels serve important roles in the excitation-contraction coupling of cardiac myocytes. Previous studies have shown that the overexpression or activation of intermediate-conductance calcium-activated potassium channel (SK4, encoded by KCNN4) in embryonic stem cell-derived cardiomyocytes can significantly increase their automaticity. The mechanism underlying this effect is hypothesized to be associated with the activation of hyperpolarization-activated cyclic nucleotide-gated channel 2 (Hcn2). The aim of the present study was to explore whether a biological pacemaker could be constructed by overexpressing SK4 alone or in combination with Hcn2 in a rat model. Ad-green fluorescent protein (GFP), Ad-KCNN4 and ad-Hcn2 recombinant adenoviruses were injected into the left ventricle of Sprague-dawley rat hearts. The rats were divided into a GFP group (n=10), an SK4 group (n=10), a HCN2 group (n=10) and an SK4 + HCN2 (SK4/Hcn2) group (n=10). The isolated hearts were perfused at 5-7 days following injection, and a complete heart block model was established. Compared with the GFP group, overexpressing SK4 alone did not significantly increase the heart rate after establishment of a complete heart block model [98.1±8.9 vs. 96.7±7.6 beats per min (BPM)], The heart rates in the SK4/Hcn2 (139.9±21.9 BPM) and HCN2 groups (111.7±5.5 BPM) were significantly increased compared with the GFP and SK4 groups, and the heart rates in the SK4/Hcn2 group were significantly increased compared with the SK4 or Hcn2 groups. In the HCN2 (n=8) and the SK4/HCN2 (n=7) groups, the shape of the spontaneous ventricular rhythm was the same as the pacing-induced ectopic rhythm in the transgenically altered site. By contrast, these rhythms were different in the SK4 (n=10) and GFP (n=10) groups. There were no significant differences in action potential duration alternans or ventricular arrhythmia inducibility between the four groups (all P>0.05). Western blotting, reverse transcription-quantitative Pcr and immunohistochemistry analyses showed that the expression levels of SK4 and Hcn2 were significantly increased at the transgene site. Biological pacemaker activity could be successfully generated by co-overexpression of SK4 and Hcn2 without increasing the risk of ventricular arrhythmias. The overexpression of SK4 alone is insufficient to generate biological pacemaker activity. The present study provided evidence that SK4 and Hcn2 combined could construct an ectopic pacemaker, laying the groundwork for the development of improved biological pacing mechanisms in the future.

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“…Even though directed cardiomyogenesis from fibroblasts was significantly enhanced in the last few years by reprogramming with several cardiopoietic transcription factor combinations (Ieda et al, 2010 ; Inagawa et al, 2012 ; Protze et al, 2012 ; Qian et al, 2012 ; Christoforou et al, 2013 ), targeted differentiation of fibroblasts or working cardiomyocytes into PCs, particularly SAN and AVN cells, remains to be poorly studied. It is known that PC development and differentiation are significantly modulated by specific transcriptional regulators, among them SHOX2, TBX3, TBX5, and TBX18 (Blaschke et al, 2007 ; Christoffels et al, 2010 ; Munshi, 2012 ; Cho, 2015 ; Gorabi et al, 2019a , b ; Raghunathan et al, 2020 ; van Eif et al, 2020 ).…”

Section: Approaches For the Engineering Of Biological Pacemakersmentioning

confidence: 99%

Bioengineering the Cardiac Conduction System: Advances in Cellular, Gene, and Tissue Engineering for Heart Rhythm Regeneration

Naumova

Iop

2021

Front. Bioeng. Biotechnol.

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Heart rhythm disturbances caused by different etiologies may affect pediatric and adult patients with life-threatening consequences. When pharmacological therapy is ineffective in treating the disturbances, the implantation of electronic devices to control and/or restore normal heart pacing is a unique clinical management option. Although these artificial devices are life-saving, they display many limitations; not least, they do not have any capability to adapt to somatic growth or respond to neuroautonomic physiological changes. A biological pacemaker could offer a new clinical solution for restoring heart rhythms in the conditions of disorder in the cardiac conduction system. Several experimental approaches, such as cell-based, gene-based approaches, and the combination of both, for the generation of biological pacemakers are currently established and widely studied. Pacemaker bioengineering is also emerging as a technology to regenerate nodal tissues. This review analyzes and summarizes the strategies applied so far for the development of biological pacemakers, and discusses current translational challenges toward the first-in-human clinical application.

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Functional biological pacemaker generation by T-Box18 protein expression via stem cell and viral delivery approaches in a murine model of complete heart block

Cited by 20 publications

References 30 publications

Reciprocal interaction between IK1 and If in biological pacemakers: A simulation study

Reciprocal interaction between IK1 and If in biological pacemakers: A simulation study

Overexpression of the medium‑conductance calcium‑activated potassium channel (SK4) and the HCN2 channel to generate a biological pacemaker

Bioengineering the Cardiac Conduction System: Advances in Cellular, Gene, and Tissue Engineering for Heart Rhythm Regeneration

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