Mitochondrial Metabolism Modulates Differentiation and Teratoma Formation Capacity in Mouse Embryonic Stem Cells

Relatively little is known regarding the role of mitochondrial metabolism in stem cell biology. Here we demonstrate that mouse embryonic stem cells sorted for low and high resting mitochondrial membrane potential (ΔΨmL and ΔΨmH) are indistinguishable morphologically and by the expression of pluripot...

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Published inThe Journal of biological chemistry Vol. 283; no. 42; pp. 28506 - 28512
Main Authors Schieke, Stefan M., Ma, Mingchao, Cao, Liu, McCoy, J. Philip, Liu, Chengyu, Hensel, Nancy F., Barrett, A. John, Boehm, Manfred, Finkel, Toren
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 17.10.2008
American Society for Biochemistry and Molecular Biology
Subjects
Animals
Cell Differentiation
Cell Line
Cell Nucleus - metabolism
Embryonic Stem Cells - cytology
Male
Membrane Potentials
Metabolism and Bioenergetics
Mice
Mice, SCID
Mitochondria - metabolism
Models, Biological
Oxygen - metabolism
Oxygen Consumption
Protein Kinases - metabolism
Teratoma - metabolism
Teratoma - pathology
TOR Serine-Threonine Kinases
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Summary:Relatively little is known regarding the role of mitochondrial metabolism in stem cell biology. Here we demonstrate that mouse embryonic stem cells sorted for low and high resting mitochondrial membrane potential (ΔΨmL and ΔΨmH) are indistinguishable morphologically and by the expression of pluripotency markers, whereas markedly differing in metabolic rates. Interestingly, ΔΨmL cells are highly efficient at in vitro mesodermal differentiation yet fail to efficiently form teratomas in vivo, whereas ΔΨmH cells behave in the opposite fashion. We further demonstrate that ΔΨm reflects the degree of overall mammalian target of rapamycin (mTOR) activation and that the mTOR inhibitor rapamycin reduces metabolic rate, augments differentiation, and inhibits tumor formation of the mouse embryonic stem cells with a high metabolic rate. Taken together, our results suggest a coupling between intrinsic metabolic parameters and stem cell fate that might form a basis for novel enrichment strategies and therapeutic options.
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Both authors contributed equally to this work.
2 To whom correspondence may be addressed: Bldg. 10/CRC 5-3132, 10 Center Dr. Bethesda, MD 20892. E-mail: Manfred.Boehm@nih.gov. 3 To whom correspondence may be addressed: Bldg. 10/CRC 5-3330, 10 Center Dr. Bethesda, MD 20892. E-mail: finkelt@nih.gov.
This work was authored, in whole or in part, by National Institutes of Health staff. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M802763200