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

24 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

Fingerprint

Phenanthrolines
Tissue Engineering
Tissue engineering
Molecules
Assays
Mesenchymal Stromal Cells
Blood vessels
Microarrays
Modulators
Screening
Repair
Genes
Chemical activation
Cells
Throughput
Tissue
Interleukin-8
High-Throughput Screening Assays
Incubators
Immunomodulation

Keywords

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

Cite this

Doorn, J., Fernandes, H. A. M., Le, B. Q., van de Peppel, J., van Leeuwen, J. P. T. M., De Vries, M. R., ... de Boer, J. (2013). A small molecule approach to engineering vascularized tissue. Biomaterials, 34(12), 3053-3063. https://doi.org/10.1016/j.biomaterials.2012.12.037
Doorn, Joyce ; Fernandes, Hugo A.M. ; Le, Bach Q. ; van de Peppel, Jeroen ; van Leeuwen, Johannes P.T.M. ; De Vries, Margreet R. ; Aref, Zeen ; Quax, Paul H.A. ; Myklebost, Ola ; Saris, Daniël B.F. ; van Blitterswijk, Clemens ; de Boer, Jan. / A small molecule approach to engineering vascularized tissue. In: Biomaterials. 2013 ; Vol. 34, No. 12. pp. 3053-3063.
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Doorn, J, Fernandes, HAM, Le, BQ, van de Peppel, J, van Leeuwen, JPTM, De Vries, MR, Aref, Z, Quax, PHA, Myklebost, O, Saris, DBF, van Blitterswijk, C & de Boer, J 2013, 'A small molecule approach to engineering vascularized tissue' Biomaterials, vol. 34, no. 12, pp. 3053-3063. https://doi.org/10.1016/j.biomaterials.2012.12.037

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

In: Biomaterials, Vol. 34, No. 12, 29.01.2013, p. 3053-3063.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - A small molecule approach to engineering vascularized tissue

AU - Doorn, Joyce

AU - Fernandes, Hugo A.M.

AU - Le, Bach Q.

AU - van de Peppel, Jeroen

AU - van Leeuwen, Johannes P.T.M.

AU - De Vries, Margreet R.

AU - Aref, Zeen

AU - Quax, Paul H.A.

AU - Myklebost, Ola

AU - Saris, Daniël B.F.

AU - van Blitterswijk, Clemens

AU - de Boer, Jan

PY - 2013/1/29

Y1 - 2013/1/29

N2 - 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.

AB - 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.

KW - IR-83684

KW - METIS-293912

KW - Angiogenesis

KW - Mesenchymal stem cells

KW - Stem cell

KW - Cell signaling

U2 - 10.1016/j.biomaterials.2012.12.037

DO - 10.1016/j.biomaterials.2012.12.037

M3 - Article

VL - 34

SP - 3053

EP - 3063

JO - Biomaterials

JF - Biomaterials

SN - 0142-9612

IS - 12

ER -

Doorn J, Fernandes HAM, Le BQ, van de Peppel J, van Leeuwen JPTM, De Vries MR et al. A small molecule approach to engineering vascularized tissue. Biomaterials. 2013 Jan 29;34(12):3053-3063. https://doi.org/10.1016/j.biomaterials.2012.12.037