MSCs protect endothelial cells from inflammatory injury partially by secreting STC1

Highlights

• MSCs ameliorate inflammatory factor induced endothelial damage.

• MSCs protect HUVECs from inflammatory injury partially by secreting STC1.

• STC1 up-regulated UCP2 in HUVECs and subsequently reduced ROS accumulation and inflammation cascade.

• MSCs may be potential for diabetic vascular complications therapy.

Abstract

Inflammatory factors play an important role in the pathogenesis of diabetic vascular complications. Considerable interest in the therapeutic potential of mesenchymal stem cells (MSCs) has recently arisen. The purposes of this study were to investigate the effects of MSCs on endothelial cells under inflammatory conditions and to determine the relevant mechanism underlying these effects. In vitro, after TNF-α stimulation, MSCs-CM treatment significantly restored cell viability, reduced THP-1 cell adhesion and enhanced tube formation capacity via inhibiting ROS overproduction and NF-κB activation, subsequently down-regulating adhesion molecules and chemokines. These effects may be partially due to the up-regulation of uncoupling protein 2 (UCP2) in HUVECs that was induced by the secretion of stanniocalcin 1 (STC1) from MSCs. In vivo, MSCs transplantation ameliorated the progression of diabetes-associated vascular dysfunction by reducing ROS production and down-regulating the expression of adhesion molecules. These results suggest that MSCs protect HUVECs from inflammatory injury partially by secreting STC1. MSCs may be a potential therapeutic approach for the treatment of diabetic vascular complications.

Introduction

There are approximately 415 million people living with diabetes mellitus worldwide. Diabetes and related complications account for the majority of total expenditures on diabetes health care. Vascular complications are the principal causes of death and disability in diabetes patients [[1], [2], [3], [4]]. Along with hyperglycaemia, insulin resistance, and dyslipidaemia, proinflammatory factors play an important role in the progression of diabetic vascular diseases [5].

Recent studies have provided compelling evidence that diabetic vascular complications are associated with inflammatory status and are enhanced by inflammatory cytokines [6]. Inflammatory cytokines such as TNF-α could lead to the overproduction of reactive oxygen species (ROS) and further activate the NF-κB pathway and other proinflammatory signalling pathways [2,7,8]. The subsequent up-regulation of the proinflammatory genes E-selectin, MCP-1, VCAM-1, and ICAM-1 via NF-κB activation leads to endothelial dysfunction [9]. These events subsequently induce leukocyte adhesion, rolling, and diapedesis, along with the formation of foam cells in the sub-endothelial layer. Foam cell-derived proinflammatory cytokines accelerate vascular inflammation and the proliferation of smooth muscle cells, promoting the progression of vascular diseases [10].

Traditional treatments for diabetic complications have failed to achieve satisfactory results. Drugs including aspirin and low-molecular-weight heparin (LMWH) were suggested to reduce vascular damage, but the prognosis associated with these drugs is inadequate, and some patients experience serious side effects from these drugs [[11], [12], [13]]. Therefore, new therapies for diabetic complications are needed. Recently, there has been considerable interest in the therapeutic potential of mesenchymal stem cells (MSCs) for the treatment of multiple diseases [[14], [15], [16], [17], [18]]. MSCs have been shown to possess immuno-modulatory, anti-apoptotic and anti-oxidant properties, which suggest their value in clinical applications [[19], [20], [21]]. However, MSCs exhibit protective effects without long-term engraftment in the recipient [22]. The secretion of multiple immuno-modulatory agents and trophic factors is believed to be the main mechanism by which MSCs achieve their therapeutic effects [22,23].

Thus, the aim of this study was to evaluate the potential beneficial effects of MSCs-CM against inflammatory factor-induced endothelial injury.