Abstract 19485: Mesenchymal Stem Cell Transplantation Attenuates Venous Stenosis of Hemodialysis Vascular Access Arteriovenous Fistula by Inhibition of Macrophage PPAR-γ Expression
Arteriovenous fistula (AVF) is the preferred vascular access for patients undergoing hemodialysis and the majority of AVFs fail because of venous intimal hyperplasia (VNH). Previous results of our lab indicate that human adipose tissue-derived mesenchymal stem cell (MSC) transplantation to the adventitia of the outflow vein of AVF attenuates VNH in immunodeficient mice. Therefore, to explore the molecular mechanisms of this observation, we performed RNA-seq transcriptome analysis of the outflow veins of AVFs excised from the C57BL/6 mice with chronic kidney disease (CKD) after adventitial transplantation of MSCs from the donor inbred C57BL/6 mice. Gene expression profile identified 37 genes that were up regulated and 180 were down regulated in the outflow veins of AVFs transplanted with MSCs compared to controls [fold change >2; RPKM >0.1; p<0.05]. Gene enrichment and functional analyses for transcription factors predicted that 22% of total genes (217) are regulated by PPAR-γ and its expression was significantly down regulated in MSC transplanted vessels. Results from RT-qPCR analysis confirmed this observation as PPAR-γ was significantly down regulated in MSC transplanted outflow veins of AVFs compared to controls. MSC transplantation significantly decreased CD68 staining in the outflow veins of AVFs compared to control mice. We determined the expression patterns of PPAR-γ using immunohistochemistry on human vein sections of failed fistulas and identified that it was significantly elevated in CD68 positive cells compared to normal veins. In vitro studies revealed that PMA induced monocyte to macrophage differentiation was inhibited when cultured in conditioned media (CM) from hypoxic human MSCs. In line with these results, expression of PPAR-γ, CD36, and IL-1β was down regulated, while the monocyte marker CD14 increased in THP-1 cells treated with CM+PMA compared to cells in control media with PMA. These results suggest that MSC transplantation reduces VNH by inhibiting macrophage differentiation by suppressing PPAR-γ gene expression and attenuating macrophage differentiation.
Author Disclosures: S. Kialri: None. B. Yang: None. D. McCall: None. A. Dietz: None. A. Van Wijnen: None. R. Vazquez-Padron: None. S. Misra: Research Grant; Significant; Funded by NIH:2 R01 HL098967-06A1.
- © 2016 by American Heart Association, Inc.