Pacemaking Effects Of Tbx18 Conditioned Cardiomyocytes Derived Exosomes In Rats With Heart Block

Background:Cardiac pacing is an effective treatment of bradyarrhythmias and biological pacemaker is a focus in current research.Somatic reprogramming by re-expression of the pacemaker-specific transcription factor Tbox 18(Tbx18)via adenovirus has been shown to convert ventricular cardiomyocytes into pacemaker cells in complete heart block animal models.But there are limitations of adenovirus as a vector.Exosomes are nanosized particles that are secreted by cells,transmitting information from cell to cell.The information inside exosomes includes proteins and RNA payloads.As a kind of compatible,safe and non-toxic vesicle,exosomes has been widely used as a vector in tumor-targeted drug transport but rarely in the field of cardiac reprogramming.Therefore,we hypothesized that exosomes can be a potential novel,efficient and safe vector to deliver Tbx18 for cardiac reprogramming and to explore the involved mechanisms.Methods and results:Exosomes were collected from culture medium of NRVMs(neonatal rat ventricular myocytes)that were transduced with either control Ad-GFP or Ad-Tbx18 virus,and injected into adult rat hearts.72 h post-exosome injection,heart block was induced in the rats by I.V.injection of acetylcholine chloride.Biological pacemaker activity,originating from the intramyocardial injection site,was evident in Tbx18-NRVMs derived exosomes(Tbx18-Exos)-treated animals at 72 hours by their distinctive morphology and correction of a complete heart block.Furthermore,in vitro studies showed that treatment of naive NRVMs with Tbxl8-Exos led to enhanced autonomic responses and superior chronotropy,as compared to control exosome-treated NRVMs.Conclusion:Tbx18-Exos can induce cardiac reprogramming and produce pacemaking effects.It provides a new method and approach for the treatment of heart block related diseases.