Mesenchymal Stem Cells Stabilize Atherosclerotic Vulnerable Plaque by Anti-Inflammatory Properties.
OBJECTIVE
Formation and progression of atherosclerotic vulnerable plaque (VP) is the primary cause of many cardio-cerebrovascular diseases such as acute coronary syndrome and stroke. It has been reported that bone marrow mesenchymal stem cells (MSC) exhibit protective effects against many kinds of diseases including myocardial infarction. Here, we examined the effects of intravenous MSC infusion on a VP model and provide novel evidence of its influence as a therapy in this animal disease model.


METHODS
Thirty healthy male New Zealand white rabbits were randomly divided into a MSC, VP or stable plaque (SP) group (n = 10/group) and received high fat diet and cold-induced common carotid artery intimal injury with liquid nitrogen to form atherosclerotic plaques. Serum hs-CRP, TNF-α, IL-6 and IL-10 levels were measured by ELISA at 1, 2, 3, 7, 14, 21 and 28 days after MSC transplantation. The animals were sacrificed at 4 weeks after MSC transplantation. Lesions in the right common carotid were observed using H&E and Masson staining, and the fibrous cap/lipid core ratio of atherosclerotic plaques were calculated. The expression of nuclear factor κB (NF-κB) and matrix metalloproteinase 1, 2, 9 (MMP-1,2,9) in the plaque were detected using immunohistochemistry, and apoptotic cells in the plaques were detected by TUNEL. In addition, the level of TNF-α stimulated gene/protein 6 (TSG-6) mRNA and protein were measured by quantitative Real-Time PCR and Western blotting, respectively.


RESULTS
Two rabbits in the VP group died of lung infection and cerebral infarction respectively at 1 week after plaque injury by liquid nitrogen. Both H&E and Masson staining revealed that the plaques from the SP and MSC groups had more stable morphological structure and a larger fibrous cap/lipid core ratio than the VP group. Serum hs-CRP, TNF-α and IL-6 were significantly down-regulated, whereas IL-10 was significantly up-regulated in the MSC group compared with the VP group. .Immunohistochemistry analysis revealed that NF-κB and MMP expression was reduced in the MSC and SP groups compared to the VP group. Cell apoptosis decreased significantly in both the MSC and SP groups in comparison to the VP group. TSG-6 mRNA and protein expression were higher in the plaques of the MSC group compared to the VP and SP groups.


CONCLUSIONS
Our study results suggest that MSC transplantation can effectively stabilize vulnerable plaques in atherosclerotic rabbits. This may potentially offer a new clinical application of MSC in atherosclerosis.
College of Medicine, Zhejiang University, Hangzhou, 310009, China; Department of Cardiology, Ningbo First Hospital, Ningbo, 315000, China.
Shuang-shuang
SS
Wang
Department of Spine Surgery, Affiliated Hospital of Medical College of Ningbo University, Ningbo 315000, China.
Si-wang
SW
Hu
Chinese PLA 305 hospital, Beijing 100017, China.
Qing-hua
QH
Zhang
Chinese PLA 305 hospital, Beijing 100017, China.
Ai-xiang
AX
Xia
Chinese PLA 305 hospital, Beijing 100017, China.
Zhi-xin
ZX
Jiang
Department of Cardiology, Ningbo First Hospital, Ningbo, 315000, China.
Xiao-min
XM
Chen
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000502:physiology; D050197:Atherosclerosis / Q000473:pathology / Q000628:therapy*; D002097:C-Reactive Protein / Q000378:metabolism; D002316:Cardiotonic Agents / Q000627:therapeutic use; D020212:Carotid Artery Injuries / Q000628:therapy; D015815:Cell Adhesion Molecules / Q000235:genetics; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D002561:Cerebrovascular Disorders / Q000517:prevention & control / Q000628:therapy*; D004195:Disease Models, Animal; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells; D016328:NF-kappa B / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000628:therapy*; D012333:RNA, Messenger / Q000235:genetics; D011817:Rabbits; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D000893:Anti-Inflammatory Agents; D002316:Cardiotonic Agents; D015815:Cell Adhesion Molecules; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D002097:C-Reactive Protein; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1