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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)493-502
Number of pages10
JournalExperimental and Molecular Medicine
Volume54
Issue number4
DOIs
StatePublished - Apr 2022
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

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