Increased predominance of the matured ventricular subtype in embryonic stem cell-derived cardiomyocytes in vivo

Hajime Ichimura,Mitsuhiko Yamada,Naoko Shiba,Shin Kadota,Kenji Okada,Shinichiro Chuma,Shugo Tohyama,Yuji Shiba,Kuniaki Ito,Toshihide Kashihara,Koichiro Kuwahara,Yuki Tanaka,Tatsuichiro Seto,Hideki Kobayashi

doi:10.1038/s41598-020-68373-9

Abstract

Accumulating evidence suggests that human pluripotent stem cell-derived cardiomyocytes can affect “heart regeneration”, replacing injured cardiac scar tissue with concomitant electrical integration. However, electrically coupled graft cardiomyocytes were found to innately induce transient post-transplant ventricular tachycardia in recent large animal model transplantation studies. We hypothesised that these phenomena were derived from alterations in the grafted cardiomyocyte characteristics. In vitro experiments showed that human embryonic stem cell-derived cardiomyocytes (hESC-CMs) contain nodal-like cardiomyocytes that spontaneously contract faster than working-type cardiomyocytes. When transplanted into athymic rat hearts, proliferative capacity was lower for nodal-like than working-type cardiomyocytes with grafted cardiomyocytes eventually comprising only relatively matured ventricular cardiomyocytes. RNA-sequencing of engrafted hESC-CMs confirmed the increased expression of matured ventricular cardiomyocyte-related genes, and simultaneous decreased expression of nodal cardiomyocyte-related genes. Temporal engraftment of electrical excitable nodal-like cardiomyocytes may thus explain the transient incidence of post-transplant ventricular tachycardia, although further large animal model studies will be required to control post-transplant arrhythmia.

Highlights

Accumulating evidence suggests that human pluripotent stem cell-derived cardiomyocytes can affect “heart regeneration”, replacing injured cardiac scar tissue with concomitant electrical integration
Discussion hPSC-CMs are considered to plausibly contribute to the post-transplant ventricular tachycardia (VT) observed in large animal models through increased automaticity as they exhibit an immature phenotype[19] with rapid spontaneous beating r ate[20,21] and contain nodal-like cardiomyocytes[22]
HESC-derived working-type cardiomyocytes, as well as in vitro nodal-like cardiomyocytes beat at 100 ± 5 and 256 ± 55 beats/min, respectively, which are much faster than the rate of the adult human heart

Summary

Introduction

Accumulating evidence suggests that human pluripotent stem cell-derived cardiomyocytes can affect “heart regeneration”, replacing injured cardiac scar tissue with concomitant electrical integration. Transplantation studies of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) were performed initially in small animal models, in which human embryonic stem cell-derived cardiomyocytes (hESC-CMs) engrafted and survived in the injured heart[2], restored contractile function[3,4], and electrically integrated with host cardiomyocytes[5,6] In these and other small animal s tudies[7], ventricular arrhythmia caused by the transplantation of hPSC-CMs was not detected, likely owing to the much faster heart rate of the host species than that of graft cardiomyocytes.

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Results

Conclusion