Effect of TGF-β1 on the Migration and Recruitment of Mesenchymal Stem Cells after Vascular Balloon Injury: Involvement of Matrix Metalloproteinase-14.

Wei Zhao,Wenjie Zhang,Juncang Duan,Lianghai Wang,Jin Zhao,Ruixue Liu,Kejian Liu,Weihua Liang,Feng Li,Lijuan Pang,Chengyan Wang,Yan Qi,Shugang Li,Hong Zou,Jinfang Jiang,Cuilei Wei

doi:10.1038/srep21176

Abstract

Restenosis or occlusion after vascular procedures is ascribed to intimal hyperplasia. Transforming growth factor (TGF)-β1 is involved in recruitment of mesenchymal stem cells (MSCs) following arterial injury, and its release from latent TGF-binding protein by matrix metalloproteinase (MMP)-14-induced proteolysis contributes to neointima formation. However, the relationship between MMP-14 and TGF-β1 activation in restenosis is unknown. This study investigated the relationship using a rat model of balloon-induced injury. Rats were assigned to vehicle-, SB431542 (SB)-, or recombinant human (rh)TGF-β1-treated groups and examined at various time points after balloon-induced injury for expression of TGF-β1/Smad signalling pathway components, MMP-14 and MSCs markers including Nestin, CD29, and Sca1+CD29+CD11b/c−CD45−. Intimal hyperplasia was reduced in SB- and rhTGF-β1-treated rats. The expression of TGF-β1, TGF-β1RI, and Smad2/3 was decreased, but the levels of phosphorylated Smad2/3 were higher in SB-treated rats than vehicle-treated after 7 days to 14 days. rhTGF-β1 administration decreased the expression of TGF-β1/Smad pathway proteins, except for TGF-β1RI. Nestin and CD29 expression and the number of Sca1+CD29+CD11b−CD45− cells were reduced, whereas MMP-14 expression was increased after SB431542 and rhTGF-β1 administration. These results suggest that TGF-β1/Smad signalling and MMP-14 act to recruit MSCs which differentiate to vascular smooth muscle cells and mesenchymal-like cells that participate in arterial repair/remodelling.

Highlights

The origin and function of cells involved in neointimal formation are not known
These results demonstrated that inhibitor of Transforming growth factor (TGF)-β 1 superfamily type I activin receptor-like kinase receptor blocked neointimal formation and vascular restenosis after arterial injury and that rhTGF-β 1 treatment did not induce neointimal formation
We found that the number mesenchymal stem cells (MSCs) of Sca1 + CD29 + CD11b/c − CD45− which are the markers of MSCs49,50 was elevated in the peripheral blood and bone marrow starting 1 day after injury and lasting up to 14 days

Summary

Introduction

The origin and function of cells involved in neointimal formation are not known. It is widely acknowledged that vascular smooth muscle cells (VSMC) are activated after arterial injury and induce neointimal formation through migration and proliferation[8]. Evaluating the role of activated TGF-β 1 in the migration and differentiation of MSCs may provide insights into the repair and remodelling of cardiac tissue. Extracellular matrix (ECM) molecules play an important role in restenosis after intimal injury[16] by providing a supportive matrix scaffold for cells and supplying growth factors. Understanding the relationship between TGF-β 1 and MMP-14 and their potential roles in MSCs recruitment can provide important insights into the mechanism underlying restenosis and neointimal formation. The expressed components of TGF-β /Smad signalling pathway and MMP-14 and their effects on MSCs in neointimal formation have been examined in a rat model that has left carotid arterial balloon injury by administrating inhibitor of TGF-β 1 superfamily type I activin receptor-like kinase (ALK) receptor SB431542 (SB) or recombinant human (rh)TGF-β 1. The findings presented are novel and may shed light on a possible role of TGF-β 1 in cardiac remodelling, which has the potential in the prevention and/or treatment of post-operative restenosis in humans

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