Mesenchymal Stem Cells Reduce Murine Atherosclerosis Development.
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.
Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
Vanessa
V
Frodermann
Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
Janine
J
van Duijn
Department of Immunohematology &Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Melissa
M
van Pel
Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
Peter J
PJ
van Santbrink
Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
Ilze
I
Bot
Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
Johan
J
Kuiper
Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.|Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
Saskia C A
SC
de Jager
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D004032:Diet; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008264:Macrophages; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
D011973:Receptors, LDL