Mesenchymal Stem Cells Reduce Murine Atherosclerosis Development

Vanessa Frodermann,Ilze Bot,Saskia C A De Jager,Peter J Van Santbrink,Johan Kuiper,Melissa Van Pel,Janine Van Duijn

doi:10.1038/srep15559

Abstract

Mesenchymal stem cells (MSCs) have regenerative properties, but recently they were also found to have immunomodulatory capacities. We therefore investigated whether MSCs could reduce atherosclerosis, which is determined by dyslipidaemia and chronic inflammation. We adoptively transferred MSCs into low-density lipoprotein-receptor knockout mice and put these on a Western-type diet to induce atherosclerosis. Initially after treatment, we found higher levels of circulating regulatory T cells. In the long-term, overall numbers of effector T cells were reduced by MSC treatment. Moreover, MSC-treated mice displayed a significant 33% reduction in circulating monocytes and a 77% reduction of serum CCL2 levels. Most strikingly, we found a previously unappreciated effect on lipid metabolism. Serum cholesterol was reduced by 33%, due to reduced very low-density lipoprotein levels, likely a result of reduced de novo hepatic lipogenesis as determined by a reduced expression of Stearoyl-CoA desaturase-1 and lipoprotein lipase. MSCs significantly affected lesion development, which was reduced by 33% in the aortic root. These lesions contained 56% less macrophages and showed a 61% reduction in T cell numbers. We show here for the first time that MSC treatment affects not only inflammatory responses but also significantly reduces dyslipidaemia in mice. This makes MSCs a potent candidate for atherosclerosis therapies.

Highlights

In recent years the immunomodulatory capacity of Mesenchymal stem cells (MSCs) has been increasingly appreciated
In agreement with previous studies[1,16,18,19], we describe that MSCs can reduce the production of pro-inflammatory cytokines by dendritic cells (DCs) and dramatically inhibit T cell proliferation in vitro
We further show that adoptive transfer of MSCs into LDLr KO mice results in an overall reduced inflammatory state, as measured by reduced circulating IFN-γ and increased IL-10 levels

Summary

Introduction

In recent years the immunomodulatory capacity of MSCs has been increasingly appreciated. DCs are present within lesions or can arise from blood-derived precursors Both macrophages and DCs express scavenger receptors enabling the uptake of oxLDL and foam cell formation and toll-like receptors, which mediate activation of the antigen-presenting cells and production of pro-inflammatory cytokines. IFN-γ promotes vascular inflammation by enhancing maturation and activation of antigen-presenting cells, increasing macrophage lipid uptake, reducing collagen production by smooth muscle cells, and enhancing expression of endothelial adhesion molecules, which subsequently stimulates leukocyte recruitment to the lesions[26]. Due to the key role of inflammatory processes in the initiation and progression of atherosclerosis, adoptive transfer of MSCs, which have the capacity to modulate and reduce inflammation, may be a therapeutic approach to treat atherosclerosis. We show to our knowledge for the first time that MSCs in addition to their immunomodulatory capacity can significantly reduce dyslipidemia, establishing the multifactorial therapeutic potential of MSCs to inhibit atherogenesis

Methods

Results

Conclusion