A small molecule approach to engineering vascularized tissue.
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% O(2)). 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.
MIRA Institute for Biomedical Technology and Technical Medicine, Department of Tissue Regeneration, University of Twente, Enschede, The Netherlands.
Joyce
J
Doorn
Hugo A M
HA
Fernandes
Bach Q
BQ
Le
Jeroen
J
van de Peppel
Johannes P T M
JP
van Leeuwen
Margreet R
MR
De Vries
Zeen
Z
Aref
Paul H A
PH
Quax
Ola
O
Myklebost
Daniel B F
DB
Saris
Clemens A
CA
van Blitterswijk
Jan
J
de Boer
D001483:Base Sequence; D001808:Blood Vessels / Q000166:cytology*; D002460:Cell Line; D017931:DNA Primers; D020869:Gene Expression Profiling; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D054852:Small Molecule Libraries; D023822:Tissue Engineering
D017931:DNA Primers; D054852:Small Molecule Libraries