Embryonic Stem Cells/Induced Pluripotent Stem Cells

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Hypoxia Promotes Efficient Differentiation of Human Embryonic Stem Cells to Functional Endothelium†

  1. Sonia Prado-Lopez1,
  2. Ana Conesa2,
  3. Ana Armiñán3,
  4. Magdalena Martínez-Losa5,
  5. Carmen Escobedo-Lucea1,
  6. Carolina Gandia3,
  7. Sonia Tarazona2,
  8. Dario Melguizo1,
  9. David Blesa6,
  10. David Montaner2,
  11. Silvia Sanz-González4,
  12. Pilar Sepúlveda3,
  13. Stefan Götz2,
  14. José Enrique O'Connor5,
  15. Rubén Moreno1,
  16. Joaquín Dopazo2,
  17. Deborah J. Burks4,
  18. Miodrag Stojkovic1,‡,*

Article first published online: 4 JAN 2010

DOI: 10.1002/stem.295

Issue

STEM CELLS

STEM CELLS

Volume 28, Issue 3, pages 407–418, March 2010

Additional Information

How to Cite

Prado-Lopez, S., Conesa, A., Armiñán, A., Martínez-Losa, M., Escobedo-Lucea, C., Gandia, C., Tarazona, S., Melguizo, D., Blesa, D., Montaner, D., Sanz-González, S., Sepúlveda, P., Götz, S., O'Connor, J. E., Moreno, R., Dopazo, J., Burks, D. J. and Stojkovic, M. (2010), Hypoxia Promotes Efficient Differentiation of Human Embryonic Stem Cells to Functional Endothelium. STEM CELLS, 28: 407–418. doi: 10.1002/stem.295

Author Information

  1. 1

    Cellular Reprogramming Laboratory, Avenida del Autopista del Saler 16, 46013 Valencia, Spain

  2. 2

    Bioinformatic Department, Avenida del Autopista del Saler 16, 46013 Valencia, Spain

  3. 3

    Cardio-regeneration Unit, Avenida del Autopista del Saler 16, 46013 Valencia, Spain

  4. 4

    CIBERDEM and Molecular Endocrinology Laboratory, Avenida del Autopista del Saler 16, 46013 Valencia, Spain

  5. 5

    Cytomics Laboratory, and Avenida del Autopista del Saler 16, 46013 Valencia, Spain

  6. 6

    Microarray Analysis Service, Príncipe Felipe Research Center (CIPF), Avenida del Autopista del Saler 16, 46013 Valencia, Spain

  1. ‡

    Telephone: +34-96-328-96-80; Fax: +34-96-328-97-01

*Cellular Reprogramming Laboratory, Príncipe Felipe Research Center (CIPF), Avenida del Autopista del Saler 16, 46013 Valencia, Spain

  1. †

    Author contributions: S.L.P. and M.S.: Designed the experiments, performed all studies of hESC in hypoxia, and interpreted data; A.C., S.T., D. Montaner, S.G., and J.D.: Analyzed the results of the microarrays; A.A., C.G., and P.S.: Performed experiments and collected data related with transplantation of EPC/EC; M.M.L. and J.E.O.: Performed flow cytometry analysis; C.E.L., D. Melguizo, and R.M.: Prepared the ECM for differentiation of hESC; D.B.: Performed CGH-Microarray analysis; S.S.G.: Performed Western analysis; D.J.B.: Performed Western analysis, wrote the manuscript; S.P.L.: Wrote the manuscript; M.S.: Wrote the manuscript, approved the final manuscript.

Publication History

  1. Issue published online: 24 MAR 2010
  2. Article first published online: 4 JAN 2010
  3. Accepted manuscript online: 4 JAN 2010 12:00AM EST
  4. Manuscript Accepted: 21 DEC 2009
  5. Manuscript Received: 14 AUG 2009

Funded by

  • Instituto Carlos III and the Valencian Health Ministry
  • Spanish Ministry for Science and Innovation (MICINN) project. Grant Number: SAF2008-00011
  • Red de Terápia Celular (TerCell), CIBERDEM (ISCIII)
  • ISCIII project. Grant Number: EMER07/012

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Keywords:

  • Angiogenesis;
  • Vasculature;
  • Hypoxia;
  • Embryonic stem cells;
  • Development

Abstract

Early development of mammalian embryos occurs in an environment of relative hypoxia. Nevertheless, human embryonic stem cells (hESC), which are derived from the inner cell mass of blastocyst, are routinely cultured under the same atmospheric conditions (21% O2) as somatic cells. We hypothesized that O2 levels modulate gene expression and differentiation potential of hESC, and thus, we performed gene profiling of hESC maintained under normoxic or hypoxic (1% or 5% O2) conditions. Our analysis revealed that hypoxia downregulates expression of pluripotency markers in hESC but increases significantly the expression of genes associated with angio- and vasculogenesis including vascular endothelial growth factor and angiopoitein-like proteins. Consequently, we were able to efficiently differentiate hESC to functional endothelial cells (EC) by varying O2 levels; after 24 hours at 5% O2, more than 50% of cells were CD34+. Transplantation of resulting endothelial-like cells improved both systolic function and fractional shortening in a rodent model of myocardial infarction. Moreover, analysis of the infarcted zone revealed that transplanted EC reduced the area of fibrous scar tissue by 50%. Thus, use of hypoxic conditions to specify the endothelial lineage suggests a novel strategy for cellular therapies aimed at repair of damaged vasculature in pathologies such as cerebral ischemia and myocardial infarction. STEM CELLS 2010;28:407–418

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