Sry-type HMG box 18 contributes to the differentiation of bone marrow-derived mesenchymal stem cells to endothelial cells

Abstract

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. Method and Results MSCs were isolated from the bone marrow of Yucatan microswine and underwent a 10 day differentiation protocol. VEGF-165 (50 ng/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. Conclusion 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.

Atherogenic Cytokines Regulate VEGF-A-Induced Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells into Endothelial Cells

“…Our group recently demonstrated that Sox18 mediates VEGF-A-induced differentiation of bone marrow-derived MSCs into ECs [21]. In tandem with VEGF-A, IL-6 caused a dose-dependent increase in IL-6R mRNA and a dose-dependent decrease in VEGFR-2 mRNA (Figure 3(a)) and Sox18 protein (Figure 3(b)).…”

Key transcription factors in the differentiation of mesenchymal stem cells

“…We also found that the expression level of Sox18 was up regulated during the differentiation process through VEGFR-II. Additionally, we found that MSCs deficient in Sox18 maintain their undifferentiated phenotype (Ikhapoh et al, 2015). These results provided evidence that the overexpression of Sox18 in MSCs stimulates the translation of EC markers (Ikhapoh et al, 2015).…”

“…Additionally, we found that MSCs deficient in Sox18 maintain their undifferentiated phenotype (Ikhapoh et al, 2015). These results provided evidence that the overexpression of Sox18 in MSCs stimulates the translation of EC markers (Ikhapoh et al, 2015). Therefore, Sox18 is a critical regulator of MSC differentiation to ECs which can provide a new clinical application of MSC therapy in cardiovascular disease.…”

“…In our laboratory, we have been successful in differentiating MSCs into endothelial cells using gene based modifications. Using our protocol, we have identified Sox18 as a transcription factor that can be manipulated to enhance the differentiation of MSCs to ECs (Ikhapoh et al, 2015). We also found that the expression level of Sox18 was up regulated during the differentiation process through VEGFR-II.…”

Mesenchymal stromal cells’ role in tumor microenvironment: involvement of signaling pathways

“…These factors can induce profound changes in the capacity for MSC, drive its differentiation into CAFs 111,114,115 , and produce growth factors 29,35,39 and angiogenic 112,115 and metastatic cytokines 118-121 . These findings suggest that MSCs may participate in the pathogenic vicious cycle wherein tumor cells modify stromal cells, and in turn, MSCs promote malignant cell maintenance and tumor growth via plastic and biochemical changes in the tumor microenvironment ( Figure1 ).…”