A small molecule approach to engineering vascularized tissue

Joyce Doorn, Hugo A.M. Fernandes, Bach Q. Le, Jeroen van de Peppel, Johannes P.T.M. van Leeuwen, Margreet R. De Vries, Zeen Aref, Paul H.A. Quax, Ola Myklebost, Daniël B.F. Saris, Clemens van Blitterswijk, Jan de Boer

Research output: Contribution to journalArticleAcademicpeer-review

27 Citations (Scopus)

Abstract

The repertoire of growth factors determines the biological engagement of human mesenchymal stromal cells (hMSCs) in processes such as immunomodulation and tissue repair. Hypoxia is a strong modulator of the secretome and well known stimuli to increase the secretion of pro-angiogenic molecules. In this manuscript, we employed a high throughput screening assay on an hMSCs cell line in order to identify small molecules that mimic hypoxia. Importantly, we show that the effect of these small molecules was cell type/species dependent, but we identified phenanthroline as a robust hit in several cell types. We show that phenanthroline induces high expression of hypoxia-target genes in hMSCs when compared with desferoxamine (DFO) (a known hypoxia mimic) and hypoxia incubator (2% O2). Interestingly, our microarray and proteomics analysis show that only phenanthroline induced high expression and secretion of another angiogenic cytokine, interleukin-8, suggesting that the mechanism of phenanthroline-induced hypoxia is distinct from DFO and hypoxia and involves the activation of other signaling pathways. We showed that phenanthroline alone was sufficient to induce blood vessel formation in a Matrigel plug assay in vivo paving the way to its application in ischeamic-related diseases.
Original languageEnglish
Pages (from-to)3053-3063
JournalBiomaterials
Volume34
Issue number12
DOIs
Publication statusPublished - 29 Jan 2013

Keywords

  • IR-83684
  • METIS-293912
  • Angiogenesis
  • Mesenchymal stem cells
  • Stem cell
  • Cell signaling

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