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microRNA-1 enhances the angiogenic differentiation of human cardiomyocyte progenitor cells

Journal of Molecular Medicine volume 91, pages 1001–1012 (2013)Cite this article

Abstract

Instigated by the discovery of adult cardiac progenitor cells, cell replacement therapy has become a promising option for myocardial repair in the past decade. We have previously shown that human-derived cardiomyocyte progenitor cells (hCMPCs) can differentiate into cardiomyocyte-, endothelial-, and smooth muscle-like cells in vitro, and in vivo after transplantation in a mouse model of myocardial infarction, resulting in preservation of cardiac function. However, to allow successful repopulation of the injured myocardium, it is of key importance to restore myocardial perfusion by the formation of new vasculature. Several studies have shown that microRNAs regulate vascular differentiation of different stem/progenitor cells. Here, we show that miR-1 is upregulated in hCMPCs during angiogenic differentiation. Upregulation of miR-1 enhanced the formation of vascular tubes on Matrigel and within a collagen matrix, and also increased hCMPC motility, as shown by planar and transwell migration assays. By western blot, qRT-PCR and luciferase reporter assays, miR-1 was found to directly target and inhibit the expression of sprouty-related EVH1 domain-containing protein 1 (Spred1). Knocking down Spred1 phenocopies the functional effect seen for miR-1 upregulation. Using a systems biology approach, we found that in hCMPCs, miR-1 is proposed to control a network of genes predominantly involved in angiogenesis-related processes, including the Spred1 pathway. Our data shows that by upregulation of miR-1, the angiogenic differentiation of hCMPCs can be enhanced, which may be used as a new therapeutic approach to improve the efficiency of cell-based therapy for cardiac regeneration by enhancing the formation of new vasculature.

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Acknowledgments

This work was supported by the Netherlands Heart Foundation [2003B07304 to P.A.D.]; the Besluit Subsidies Investeringen Kennisinfrastructuur “Dutch Program for Tissue Engineering” [6746 to P.A.D.]; a Bekalis price (to P.A.D.). We thank Jeane Kamta and Maarten van der Kroef for technical assistance.

Conflict of Interest Disclosure Statement

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, room G02.523, 3584 CX, Utrecht, The Netherlands

    Alain van Mil, Krijn R. Vrijsen, Corina H. Metz, Pieter A. Doevendans & Joost P. Sluijter

  2. Netherlands Heart Institute, 3511 GC, Utrecht, The Netherlands

    Alain van Mil, Pieter A. Doevendans & Joost P. Sluijter

  3. Department of Molecular Cell Biology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands

    Marie-José Goumans

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  1. Alain van Mil
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  2. Krijn R. Vrijsen
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  3. Marie-José Goumans
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  4. Corina H. Metz
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  5. Pieter A. Doevendans
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  6. Joost P. Sluijter
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Correspondence to Joost P. Sluijter.

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van Mil, A., Vrijsen, K.R., Goumans, MJ. et al. microRNA-1 enhances the angiogenic differentiation of human cardiomyocyte progenitor cells. J Mol Med 91, 1001–1012 (2013). https://doi.org/10.1007/s00109-013-1017-1

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  • DOI: https://doi.org/10.1007/s00109-013-1017-1

Keywords

  • microRNA-1
  • Cardiac progenitor cell
  • Differentiation
  • Angiogenesis
  • Spred1