Endothelial progenitor cells give rise to pro-angiogenic smooth muscle-like progeny.
OBJECTIVE
Reciprocal plasticity exists between endothelial and mesenchymal lineages. For instance, mature endothelial cells adopt a smooth muscle-like phenotype through transforming growth factor beta-1 (TGFbeta1)-driven endothelial-to-mesenchymal transdifferentiation (EndMT). Peripheral blood contains circulating endothelial progenitor cells of which the endothelial colony-forming cells (ECFCs) harbour stem cell-like properties. Given the plasticity between endothelial and mesenchymal lineages and the stem cell-like properties of ECFCs, we hypothesized that ECFCs can give rise to smooth muscle-like progeny.


RESULTS
ECFCs were stimulated with TGFbeta1, after which TGFbeta signalling cascades and their downstream effects were investigated. Indeed, EndMT of ECFCs resulted in smooth muscle-like progeniture. TGFbeta1-driven EndMT is mediated by ALK5 kinase activity, increased downstream Smad2 signalling, and reduced protein levels of inhibitor of DNA-binding protein 3. ECFCs lost expression of endothelial markers and endothelial anti-thrombogenic function. Simultaneously, mesenchymal marker expression was gained, cytoskeletal rearrangements occurred, and cells acquired a contractile phenotype. Transdifferentiated ECFCs were phenotypically stable and self-sustaining and, importantly, showed fibroblast growth factor-2 and angiopoietin-1-mediated pro-angiogenic paracrine properties.


CONCLUSIONS
Our study is the first to demonstrate that ECFCs can give rise to smooth muscle-like progeny, with potential therapeutic benefits. These findings further illustrate that ECFCs are highly plastic, which by itself has implications for therapeutical use.
Moonen
Jan-Renier A J
JR
Laboratory for Cardiovascular Regenerative Medicine , NL-9713GZ Groningen, The Netherlands.
Krenning
Guido
G
Brinker
Marja G L
MG
Koerts
Jasper A
JA
van Luyn
Marja J A
MJ
Harmsen
Martin C
MC
D042683:Angiopoietin-1 / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D019070:Cell Lineage; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D005312:Fetal Blood / Q000166:cytology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D018919:Neovascularization, Physiologic; D019899:Paracrine Communication; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014661:Vasoconstriction
C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D015415:Biomarkers; D051796:Inhibitor of Differentiation Proteins; D009363:Neoplasm Proteins; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D016222:Fibroblast Growth Factor 2; C075640:ID3 protein, human; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human