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

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Hoque, A, Sivakumaran, P, Bond, ST, Ling, NXY, Kong, AM, Scott, JW, Bandara, N, Hernandez, D, Liu, G-S ORCID: 0000-0003-3379-724X, Wong, RCB, Ryan, MT, Hausenloy, DJ, Kemp, BE, Oakhill, JS, Drew, BG, Pebay, A and Lim, SY 2018 , 'Mitochondrial fission protein Drp1 inhibition promotes cardiac mesodermal differentiation of human pluripotent stem cells' , Cell Death Discovery, vol. 4 , pp. 1-13 , doi: 10.1038/s41420-018-0042-9.

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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.

Item Type: Article
Authors/Creators:Hoque, A and Sivakumaran, P and Bond, ST and Ling, NXY and Kong, AM and Scott, JW and Bandara, N and Hernandez, D and Liu, G-S and Wong, RCB and Ryan, MT and Hausenloy, DJ and Kemp, BE and Oakhill, JS and Drew, BG and Pebay, A and Lim, SY
Keywords: Mitochondria, iPSC, cardiomyocyte
Journal or Publication Title: Cell Death Discovery
Publisher: Nature Publishing Group
ISSN: 2058-7716
DOI / ID Number: 10.1038/s41420-018-0042-9
Copyright Information:

© 2018 The Authors. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/

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