title: Monocyte chemotactic protein-1 promotes the myocardial homing of mesenchymal stem cells in dilated cardiomyopathy.
abstract: Dilated cardiomyopathy (DCM) is the most common form of non-ischemic cardiomyopathy that leads to heart failure. Mesenchymal stem cells (MSCs) are under active investigation currently as a potential therapy for DCM. However, little information is available about the therapeutic potential of intravenous administration of MSCs for DCM. Moreover, how MSCs home to the myocardium in DCM is also unclear. DCM was induced by intraperitoneally administering Doxorubicin and MSCs or vehicles were infused through the internal jugular vein. Cardiac functions including the percentage of fractional shortening, left ventricular diastolic dimension, left ventricular end-diastolic pressure, and left ventricular maximum dp/dt were evaluated by echocardiographic and hemodynamic studies. Fibrosis was determined by Masson's trichrome staining. The mRNA expression levels of monocyte chemotactic protein-1 (MCP-1), stromal cell-derived factor-1 (SDF-1), macrophage inflammatory protein-1α (MIP-1α), and monocyte chemotactic protein-3 (MCP-3) were determined using real time polymerase chain reactions and the protein expression level of MCP-1 was detected with Western blot. The MSCs expression of C-C chemokine receptor type 2 (CCR2), a MCP-1 receptor, was confirmed by Western blot and flow cytometry analysis. The chemotactic effects of MCP-1/CCR2 were checked by assessing the migration in vitro and in vivo. MSCs transplantation improved the cardiac function and decreased the myocardial fibrosis of mice with DCM. MCP-1 was up-regulated in dilated myocardial tissue both at the mRNA and protein level while SDF-1, MIP-1α and MCP-3 remain unchanged. CCR2 was present in MSCs. MCP-1 promoted MSCs migration in vitro while CCR2 inhibition decreased the migration of MCP-1 to the dilated heart. This study provides direct evidences that peripheral intravenous infusion of MSCs can support the functional recovery of DCM. In addition, novel insights into the myocardial homing factor of MSCs in DCM are presented. Modulation of MCP-1/CCR2 signaling system might be a novel therapeutic strategy for DCM.
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China. zou.yunzeng@zs-hospital.sh.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Guo
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhang
authors.forename: Junjie
authors.initials: J
authors.lastname: Xiao
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.forename: Yong
authors.initials: Y
authors.lastname: Ye
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
authors.forename: Xinli
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D002465:Cell Movement / Q000502:physiology; D018932:Chemokine CCL2 / Q000235:genetics / Q000502:physiology*; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism; D054410:Chemokine CCL7 / Q000235:genetics / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: C491768:Ccl2 protein, mouse; C496534:Ccl3 protein, mouse; C515451:Ccl7 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054410:Chemokine CCL7; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054390:Receptors, CCR2