Key result
TBX3 and HCN2 overexpression reprograms hiPSC-derived cardiomyocytes into spontaneously depolarizing pacemaker-like cells.
Why the study?
TBX3 reprograms cardiac myocytes into cells with a sinoatrial node phenotype, but without detectable specific funny current (If).
Co-overexpression of TBX3 and HCN2 in human iPSC-derived cardiomyocytes enables the formation of spontaneous diastolic depolarization, providing a potential strategy for developing biological pacemakers.
No immediate clinical translation; leaves open whether TBX3/HCN2 yields functional If-positive pacemaker cells in vivo.
TBX3 reprograms cardiac myocytes into cells that possess sinoatrial node phenotype, but no specific funny current (If) was detected. We explore whether overexpression of TBX3 alone or combined with HCN2 can reprogram human-induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) into pacemaker-like cells. HiPSC-CMs were transfected with TBX3 and/or HCN2 in this study. Expression analysis showed that overexpression of TBX3 induces a reduced reduction expression profile of working cardiomyocytes into that of pacemaker cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and electrophysiological analyses showed a reduced expression of connexins subunits (CX40, CX43), the sodium current (SCN5A, INa), the inward rectified potassium channels (Kir2.1, IK1), and an increased expression of connexins subunits (CX30.2, CX45). No If was detected. The reduction of IK1 resulted in a more depolarized maximum diastolic potential together with an expression of If (generated by HCN2), which they work in synergy to generate spontaneous diastolic depolarization that was the most typical characteristic of pacemaker cells. In conclusion, overexpression of TBX3 and HCN2 could reprogram hiPSC-CMs into pacemaker-like cells. The ability to enable diastolic depolarization formation provides a new strategy for the construction of a biological pacemaker.
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Zhao et al. (2020) studied Biological pacemaker construction. Overexpression of TBX3 and HCN2 was evaluated on Reprogramming into pacemaker-like cells. Overexpression of TBX3 and HCN2 reprogrammed human-induced pluripotent stem cells-derived cardiomyocytes into pacemaker-like cells capable of spontaneous diastolic depolarization.
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