Mitochondrial fission protein Drp1 inhibition promotes cardiac mesodermal differentiation of human pluripotent stem cells

Cell Death Discovery. 2018;4(1):1-13 DOI 10.1038/s41420-018-0042-9

 

Journal Homepage

Journal Title: Cell Death Discovery

ISSN: 2058-7716 (Online)

Publisher: Nature Publishing Group

Society/Institution: CDD Press

LCC Subject Category: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens | Science: Biology (General): Cytology

Country of publisher: United Kingdom

Language of fulltext: English

Full-text formats available: PDF, HTML

 

AUTHORS

Ashfaqul Hoque (St Vincent’s Institute of Medical Research)
Priyadharshini Sivakumaran (St Vincent’s Institute of Medical Research)
Simon T. Bond (Molecular Metabolism and Ageing Laboratory, Baker Heart and Diabetes Institute)
Naomi X. Y. Ling (St Vincent’s Institute of Medical Research)
Anne M. Kong (St Vincent’s Institute of Medical Research)
John W. Scott (St Vincent’s Institute of Medical Research)
Nadeeka Bandara (St Vincent’s Institute of Medical Research)
Damián Hernández (Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital)
Guei-Sheung Liu (Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital)
Raymond C. B. Wong (Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital)
Michael T. Ryan (Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University)
Derek J. Hausenloy (Hatter Cardiovascular Institute, University College London)
Bruce E. Kemp (St Vincent’s Institute of Medical Research)
Jonathan S. Oakhill (St Vincent’s Institute of Medical Research)
Brian G. Drew (Molecular Metabolism and Ageing Laboratory, Baker Heart and Diabetes Institute)
Alice Pébay (Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital)
Shiang Y. Lim (St Vincent’s Institute of Medical Research)

EDITORIAL INFORMATION

Blind peer review

Editorial Board

Instructions for authors

Time From Submission to Publication: 9 weeks

 

Abstract | Full Text

Abstract Human induced pluripotent stem cells (iPSCs) are a valuable tool for studying the cardiac developmental process in vitro, and cardiomyocytes derived from iPSCs are a putative cell source for personalized medicine. Changes in mitochondrial morphology have been shown to occur during cellular reprogramming and pluripotent stem cell differentiation. However, the relationships between mitochondrial dynamics and cardiac mesoderm commitment of iPSCs remain unclear. Here we demonstrate that changes in mitochondrial morphology from a small granular fragmented phenotype in pluripotent stem cells to a filamentous reticular elongated network in differentiated cardiomyocytes are required for cardiac mesodermal differentiation. Genetic and pharmacological inhibition of the mitochondrial fission protein, Drp1, by either small interfering RNA or Mdivi-1, respectively, increased cardiac mesoderm gene expression in iPSCs. Treatment of iPSCs with Mdivi-1 during embryoid body formation significantly increased the percentage of beating embryoid bodies and expression of cardiac-specific genes. Furthermore, Drp1 gene silencing was accompanied by increased mitochondrial respiration and decreased aerobic glycolysis. Our findings demonstrate that shifting the balance of mitochondrial morphology toward fusion by inhibition of Drp1 promoted cardiac differentiation of human iPSCs with a metabolic shift from glycolysis towards oxidative phosphorylation. These findings suggest that Drp1 may represent a new molecular target for future development of strategies to promote the differentiation of human iPSCs into cardiac lineages for patient-specific cardiac regenerative medicine.