In Vivo Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Neonatal and Adult Rat Hearts

We hypothesized that the neonatal rat heart would bring transplanted human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to maturity as it grows to adult size. In neonatal rat heart, engrafted hiPSC derivatives developed partially matured myofibrils after 3 months, with increasing cell size and sarcomere length. There was no difference between grafts from hiPSC-CMs or hiPSC-derived cardiac progenitors (hiPSC-CPs) at 3 months, nor was maturation influenced by infarction. Interestingly, the infarcted adult heart induced greater human cardiomyocyte hypertrophy and induction of cardiac troponin I expression than the neonatal heart. Although human cardiomyocytes at all time points were significantly smaller than the host rat cardiomyocytes, transplanted neonatal rat cardiomyocytes reached adult size and structure by 3 months. Thus, the adult rat heart induces faster maturation than the neonatal heart, and human cardiomyocytes mature more slowly than rat cardiomyocytes. The slower maturation of human cardiomyocytes could be related to environmental mismatch or cell-autonomous factors. [Display omitted] •HiPSC-CMs and hiPSC-CPs can engraft and partially mature in neonatal rat hearts•There is greater maturation of hiPSC-CMs in adult rat hearts than in neonates•Engrafted rat cardiomyocytes reached adult size by 3 months in growing rat hearts Human iPSC-derived cardiomyocytes (hiPSC-CMs) are typically immature, resembling fetal cardiomyocytes. Three months after transplantation to neonatal and adult rat hearts, hiPSC-CMs enlarged and developed partially mature sarcomeres, with greater maturation in the adult heart. Neonatal rat cardiomyocyte grafts matured fully by 3 months, indicating that the human cells require additional time or environmental factors for full maturation.