Metabolic changes of human induced pluripotent stem cell-derived cardiomyocytes and teratomas after transplantation

Cardiac regenerative therapy using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has been applied in clinical settings. Herein, we aimed to investigate the in vivo metabolic profiles of hiPSC-CM grafts. RNA sequencing and imaging mass spectrometry were performed in the present study, which revealed that hiPSC-CM grafts matured metabolically over time after transplantation. Glycolysis, which was active in the hiPSC-CM grafts immediately after transplantation, shifted to fatty acid oxidation. Additionally, we examined the metabolic profile of teratomas that may form when non-CMs, including undifferentiated hiPSCs, remain in transplanted cells. The upregulated gene expression of amino acid transporters and the high accumulation of amino acids, such as methionine and aromatic amino acids, were observed in the teratomas. We show that subcutaneous teratomas derived from undifferentiated hiPSCs can be detected in vivo using positron emission tomography with [18F]fluorophenylalanine. These results provided insights into the clinical application of cardiac regenerative therapy. Overall design: We evaluated gene expressions of human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) tissues and hiPSC-derived teratomas by using RNA-seq two, four and twelve weeks after transplantation of hiPSC-CMs or hiPSCs to the hearts of immunodeficient mice.