Abstract 4124354: Transplantation of vascularized cardiac microtissue derived from human iPS cells improves impaired electrical conduction capacity in a porcine myocardial injury model

Abstract

Background: To realize efficient regenerative medicine using human iPS cell (hiPSC)-derived cardiac tissue, it is necessary to achieve electrical synchronization between the graft and the host heart and to improve conduction disturbances in the impaired heart. In this study, we aimed to demonstrate that the transplantation of hiPSC-derived vascularized cardiac tissue can improve these conduction disturbances using a porcine myocardial injury model. Methods: We prepared cell sheet-shaped vascularized cardiac microtissue (VCM) by seeding cardiomyocytes, endothelial cells, and vascular mural cells differentiated from hiPSCs onto temperature-responsive culture plates and thickening them using dynamic rocking culture. We induced myocardial injury (MI) via epicardial cryoablation in immunosuppressed crown minipigs and transplanted the VCMs immediately after MI induction, covering the cryoinjury-induced MI area. The pigs underwent epicardial electroanatomic mapping under sinus rhythm and epicardial pacing, both immediately before and one week after MI induction, while using amiodarone. Differences in myocardial voltages and conduction velocities were assessed between VCM and sham groups (N=3 in each group). After electroanatomic analysis, the hearts were harvested and subjected to histological examination. Results: One week after MI induction, mean voltages at the MI site decreased in both groups during sinus rhythm, remote site pacing, and combined remote and MI site pacing (11.05 to 1.74 mV, 14.26 to 3.44 mV, and 15.61 to 3.67 mV, respectively, in the VCM group; and 8.72 to 2.70 mV, 19.64 to 3.64 mV, and 14.66 to 1.96 mV, respectively, in the Sham group). Mean voltages at the remote site also decreased in both groups during the same conditions (12.57 to 4.53 mV, 10.61 to 3.38 mV, and 19.56 to 5.85 mV, respectively, in the VCM group; and 8.75 to 6.03 mV, 14.15 to 5.79 mV, and 13.67 to 6.23 mV, respectively, in the Sham group). The mean conduction velocity between the remote and MI sites was numerically higher in the VCM group compared to the Sham group (2.84 m/s vs. 1.74 m/s, respectively). Histological examination confirmed that in the VCM transplantation group, the VCM remained intact, completely covering the MI area. Conclusions: The transplantation of VCM showed a tendency to improve conduction disturbances in the porcine MI model. This suggests that the graft may synchronize with the host and function mechanically after cell transplantation.