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Cell Death Discov. 2018 Mar 5;4:39. doi: 10.1038/s41420-018-0042-9. eCollection 2018 Dec.

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

Author information

1
1St Vincent's Institute of Medical Research, Fitzroy, VIC 3065 Australia.
2
Molecular Metabolism and Ageing Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC 3004 Australia.
3
3School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW 2678 Australia.
4
4Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3065 Australia.
5
5Departments of Medicine and Surgery, University of Melbourne, Melbourne, VIC 3065 Australia.
6
6Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000 Australia.
7
Shenzhen Eye Hospital, Shenzhen, China.
8
8Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800 Australia.
9
9Hatter Cardiovascular Institute, University College London, London, WC1E 6HX UK.
10
10The National Institute of Health Research University College London Hospitals Biomedical Research Centre, London, UK.
11
11Barts Heart Centre, St Bartholomew's Hospital, London, UK.
12
12Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore.
13
13National Heart Research Institute Singapore, National Heart Centre, Singapore, Singapore.
14
14Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore.
15
15Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC 3000 Australia.
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Contributed equally

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.

Conflict of interest statement

The authors declare that they have no conflict of interest.

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