Tomatidine-stimulated maturation of human embryonic stem cell-derived cardiomyocytes for modeling mitochondrial dysfunction.

Kim, Ye Seul; Yoon, Jung Won; Kim, Dasol; Choi, Seunghak; Kim, Hyoung Kyu; Youm, Jae Boum; Han, Jin; Heo, Soon Chul; Hyun, Sung-Ae; Seo, Jung-Wook; Kim, Deok-Ho; Kim, Jae Ho

Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) have been reported to exhibit immature embryonic or fetal cardiomyocyte-like phenotypes. To enhance the maturation of hESC-CMs, we identified a natural steroidal alkaloid, tomatidine, as a new substance that stimulates the maturation of hESC-CMs. Treatment of human embryonic stem cells with tomatidine during cardiomyocyte differentiation stimulated the expression of several cardiomyocyte-specific markers and increased the density of T-tubules. Furthermore, tomatidine treatment augmented the number and size of mitochondria and enhanced the formation of mitochondrial lamellar cristae. Tomatidine treatment stimulated mitochondrial functions, including mitochondrial membrane potential, oxidative phosphorylation, and ATP production, in hESC-CMs. Tomatidine-treated hESC-CMs were more sensitive to doxorubicin-induced cardiotoxicity than the control cells. In conclusion, the present study suggests that tomatidine promotes the differentiation of stem cells to adult cardiomyocytes by accelerating mitochondrial biogenesis and maturation and that tomatidine-treated mature hESC-CMs can be used for cardiotoxicity screening and cardiac disease modeling. Heart muscle: Promoting stem cell maturation yields a better model A naturally occurring compound that promotes human heart muscle cell (cardiomyocyte) maturation could give researchers a more sophisticated model for studying drug toxicity. Researchers can use chemical signals to convert stem cells into functional cardiomyocytes, but the resulting cells lack key features of mature cells. Researchers led by Jae Ho Kim at Pusan National University, Yangsan, South Korea, have now demonstrated that treatment with the plant-derived compound tomatidine can coax such cells into a state that more closely reflects maturity. Tomatidine is known to prevent atrophy in skeletal muscle, and the researchers found that it also promotes appropriate levels of mitochondrial function and metabolic activity in human stem cell-derived cardiomyocytes. Tomatidine-treated cells also provided a superior system for modeling drug-induced heart damage, and could thus help signal potential cardiotoxicity during drug development.

Experimental & Molecular Medicine EMM, 2022, Vol 54, Issue 4, p493

1226-3613

Academic Journal

10.1038/s12276-022-00746-8