1549-4918/asset/cover.gif?v=1&s=51ac62b4272cd760b70f0cb1539035cc40743da6 "STEM CELLS")
Telephone: 34-914531200; Fax: 34 914531265
1549-4918/asset/olbannerleft.jpg?v=1&s=699114e871887e6b838f6a1c657fe256cfe127a6)
1549-4918/asset/olbannerright.gif?v=1&s=603f8f2ab5cd9d4f783c231915608956af51aeea)
Embryonic Stem Cells/Induced Pluripotent Stem Cells
You have full text access to this OnlineOpen article
Mitochondrial Reactive Oxygen Species Mediate Cardiomyocyte Formation from Embryonic Stem Cells in High Glucose†‡§
Article first published online: 6 MAY 2010
DOI: 10.1002/stem.441
Copyright © 2010 AlphaMed Press
Additional Information
How to Cite
Crespo, F. L., Sobrado, V. R., Gomez, L., Cervera, A. M. and McCreath, K. J. (2010), Mitochondrial Reactive Oxygen Species Mediate Cardiomyocyte Formation from Embryonic Stem Cells in High Glucose. STEM CELLS, 28: 1132–1142. doi: 10.1002/stem.441
- †
Author contributions: F.L.C.: collection and/or assembly of data, data analysis and interpretation, and final approval of manuscript; V.R.S.: collection and/or assembly of data, data analysis and interpretation, and final approval of manuscript; L.G.: collection and/or assembly of data, data analysis and interpretation, and final approval of manuscript; A.M.C.: conception and design, collection and/or assembly of data, data analysis and interpretation, and final approval of manuscript; K.J.M.: conception and design, collection and/or assembly of data, data analysis and interpretation, financial support, manuscript writing, and final approval of manuscript.
- ‡
First published online in STEM CELLS EXPRESS May 6, 2010.
- §
Disclosure of potential conflicts of interest is found at the end of this article.
Publication History
- Issue published online: 20 JUL 2010
- Article first published online: 6 MAY 2010
- Manuscript Accepted: 29 APR 2010
- Manuscript Received: 16 FEB 2010
Funded by
- Instituto de Salud Carlos III. Grant Number: PI0600299
- Spanish Ministry of Science and Innovation. Grant Number: SAF2009-07965
Keywords:
- Stem cells;
- Reactive oxygen species;
- Cardiomyocyte;
- Mitochondria;
- Glucose
Abstract
Accumulating evidence points to reactive oxygen species (ROS) as important signaling molecules for cardiomyocyte differentiation in embryonic stem (ES) cells. Given that ES cells are normally maintained and differentiated in medium containing supraphysiological levels of glucose (25 mM), a condition which is known to result in enhanced cellular ROS formation, we questioned whether this high glucose concentration was necessary for cardiomyocyte lineage potential. We show here that ES cells cultured in physiological glucose (5 mM), maintained their general stemness qualities but displayed an altered mitochondrial metabolism, which resulted in decreased ROS production. Furthermore, ES and induced pluripotent stem (iPS) cells differentiated in lower glucose concentrations failed to generate cardiomyocyte structures; an effect mimicked with antioxidant treatments using catalase, N-acetyl cysteine and mitoubiquinone, under high glucose conditions in ES cells. Molecular analysis revealed that ES cells differentiated in 5 mM glucose had reduced expression of the pro-cardiac NOX4 gene and diminished phosphorylation of p38 mitogen-activated protein kinase (MAPK), together with specific changes in the cardiac transcriptional network. These outcomes could be reversed by supplementation of low glucose cultures with ascorbic acid, paradoxically acting as a pro-oxidant. Furthermore, forced expression of an upstream p38 MAPK kinase (MKK6) could bypass the requirement for ROS during differentiation to cardiomyocytes under low glucose conditions, illustrating a key role for p38 in the cardiac differentiation program. Together these data demonstrate that endogenous ROS control is important for cardiomyocyte formation from ES cells, and furthermore that supraphysiological glucose, by supplying ROS, is absolutely required. STEM CELLS 2010;28:1132–1142