Mesenchymal Stem Cells Promote Infiltration Of Myeloid-Derived Suppressor Cells After Acute Myocardial Infarction Via Up-Regulation Of Multiple Cytokines

Mesenchymal stem cell (MSC) therapy improves cardiac function after myocardial infarction (MI) in part via immune modulation. Myeloid-derived suppressor cells (MDSCs), defined as cells expressing the myeloid lineage markers cluster of differentiation CD11b and granulocyte-differentiation antigen Gr-1, are presumed to be recruited to sites of inflammation. However, it is not known whether the beneficial effects of MSC therapy for MI treatment are mediated by infiltrated MDSCs in infarcted hearts. Bone marrow-derived MSCs were injected into the peri-ischemic region of the myocardium after ligation of the proximal left coronary artery in a mouse model of MI. On days 1, 3, and 7, MDSC populations in blood and infarcted myocardium were examined by flow cytometry. At 1 day after MI, the number of CD11b(+)Gr-1(+) MDSCs was increased in the ischemic myocardium of MSC-injected as compared to saline-injected mice (P < 0.001), whereas no differences were observed between the two groups on days 3 and 7. Histological analysis confirmed that MDSC recruitment to the myocardium was higher in the MSC-injected group than in the control group 1 day after MI. MSC treatment increased mRNA levels of chemokine (C-C motif) ligand 2 (CCL2), C-X-C motif chemokine (CXCL5) macrophage colony-stimulating factor (M-CSF), and cyclooxygenase 2 (COX2) in infarcted hearts. These results indicate that MSC treatment increases MDSC infiltration into the infarcted heart in the early period after MI via modulation of CCL2, CXCL5, M-CSF, and COX2 expression.