Sry-type HMG box 18 contributes to the differentiation of bone marrow-derived mesenchymal stem cells to endothelial cells.
OBJECTIVE
Mesenchymal stem cells (MSC) have shown therapeutic potential to engraft and either differentiate into or support differentiation of vascular endothelial cells (EC), smooth muscle cells and cardiomyocytes in animal models of ischemic heart disease. Following intracoronary or transendocardial delivery of MSCs, however, only a small fraction of cells engraft and the majority of those persist as an immature cell phenotype. The goal of the current study was to decipher the molecular pathways and mechanisms that control MSC differentiation into ECs. Vascular endothelial growth factor (VEGF-165) treatment is known to enhance in vitro differentiation of MSCs into ECs. We tested the possible involvement of the Sry-type HMG box (Sox) family of transcription factors in this process.


RESULTS
MSCs were isolated from the bone marrow of Yucatan microswine and underwent a 10 day differentiation protocol. VEGF-165 (50ng/ml) treatment of MSCs in vitro induced a significant increase in the protein expression of VEGFR-2, Sox9 and Sox18, in addition to the EC markers PECAM-1, VE-cadherin and vWF, as determined by Western blot or flow cytometry. siRNA-mediated knockdown of Sox18, as opposed to Sox9, in MSCs prevented VEGF-165-mediated induction of EC markers and capillary tube formation. Inhibition of VEGFR-2 signaling (SC-202850) reduced Sox18 and reduced VEGF-165-induced differentiation of MSCs to ECs.


CONCLUSIONS
Here we demonstrate that VEGF-165 mediates MSC differentiation into ECs via VEGFR-2-dependent induction of Sox18, which ultimately coordinates the transcriptional upregulation of specific markers of the EC phenotype.
Department of Medical Microbiology and Immunology Creighton University School of Medicine, Omaha, NE, USA. Electronic address: IzuagieAttairu@Creighton.edu.
Izuagie Attairu
IA
Ikhapoh
Department of Biomedical Sciences Creighton University School of Medicine, Omaha, NE, USA.
Christopher J
CJ
Pelham
Department of Medical Microbiology and Immunology Creighton University School of Medicine, Omaha, NE, USA; Department of Biomedical Sciences Creighton University School of Medicine, Omaha, NE, USA; Center for Clinical and Translational Science Creighton University School of Medicine, Omaha, NE, USA. Electronic address: dkagr@creighton.edu.
Devendra K
DK
Agrawal
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D055760:SOXF Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D013552:Swine; D013556:Swine, Miniature; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis* / Q000235:genetics
D055760:SOXF Transcription Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2
Differentiation; Endothelial cell; Growth Factor; Mesenchymal stem cell; Sox18; Sox9