Endothelial progenitor cells undergo an endothelial-to-mesenchymal transition-like process mediated by TGFbetaRI.
OBJECTIVE
Endothelial progenitor cells (EPC) have been shown to repair pulmonary endothelium, although they can also migrate into the arterial intima and differentiate into smooth muscle-like (mesenchymal) cells contributing to intimal hyperplasia. The molecular mechanisms by which this process proceeds have not been fully elucidated. Here, we study whether genes involved in the endothelial-to-mesenchymal transition (EnMT) may contribute to the mesenchymal phenotype acquisition of EPC and we evaluate whether transforming growth factor β1 (TGFβ1) is involved in this process.


RESULTS
Our results show that co-culture of EPC with smooth muscle cells (SMC) increases the expression of the mesenchymal cell markers α-smooth muscle actin, sm22-α, and myocardin, and decreases the expression of the endothelial cell marker CD31. In the same conditions, we also observed a concomitant increase in the gene expression of the EnMT-related transcription factors: slug, snail, zeb1, and endothelin-1. This indicates that mesenchymal phenotype acquisition occurred through an EnMT-like process. Inhibition of TGFβ receptor I (TGFβRI) downregulated snail gene expression, blocked the EnMT, and facilitated the differentiation of EPC to the endothelial cell lineage. Furthermore, TGFβRI inhibition decreased migration of EPC stimulated by SMC without affecting their functionality and adhesion capacity.


CONCLUSIONS
These results indicate that EPC may differentiate into SMC-like cells through an EnMT-like process and that TGFβI plays an important role in the fate of EPC.
Díez
Marta
M
Department of Pulmonary Medicine, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Ciber de Enfermedades Respiratorias, Universitat de Barcelona, Barcelona, Spain.
Musri
Melina M
MM
Ferrer
Elisabet
E
Barberà
Joan A
JA
Peinado
Víctor I
VI
D000199:Actins / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology; D006801:Humans; D008648:Mesoderm / Q000166:cytology* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D044022:Receptor, Endothelin A / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D000099152:Cadherin 5
D000199:Actins; D015703:Antigens, CD; D015820:Cadherins; D019332:Endothelin-1; D017346:Protein Serine-Threonine Kinases; D044022:Receptor, Endothelin A; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000099152:Cadherin 5; C000604407:SNAI1 protein, human