Effects of Matrix Metalloproteinases on the Performance of Platelet Fibrin Gel Spiked With Cardiac Stem Cells in Heart Repair.
Stem cells and biomaterials have been studied for therapeutic cardiac repair. Previous studies have shown the beneficial effects of platelet fibrin gel and cardiac stem cells when cotransplanted into rodent hearts with myocardial infarction (MI). We hypothesized that matrix metalloproteinases (MMPs) play an important role in such protection. Thus, the present study is designed to elucidate the effects of MMP inhibition on the therapeutic benefits of intramyocardial injection of platelet fibrin gel spiked with cardiac stem cells (cell-gel) in a rat model of acute MI. In vitro, broad-spectrum MMP inhibitor GM6001 undermines cell spreading and cardiomyocyte contraction. In a syngeneic rat model of myocardial infarction, MMP inhibition blunted the recruitment of endogenous cardiovascular cells into the injected biomaterials, therefore hindering de novo angiogenesis and cardiomyogenesis. Echocardiography and histology 3 weeks after treatment revealed that metalloproteinase inhibition diminished the functional and structural benefits of cell-gel in treating MI. Reduction of host angiogenesis, cardiomyocyte cycling, and MMP-2 activities was evident in animals treated with GM6001. Our findings suggest that MMPs play a critical role in the therapeutic benefits of platelet fibrin gel spiked with cardiac stem cells for treating MI.


CONCLUSIONS
In this study, the effects of matrix metalloproteinase inhibition on the performance of platelet gel spiked with cardiac stem cells (cell-gel) for heart regeneration are explored. The results demonstrate that matrix metalloproteinases are required for cell-gel to exert its benefits in cardiac repair. Inhibition of matrix metalloproteinases reduces cell engraftment, host angiogenesis, and recruitment of endogenous cardiovascular cells in rats with heart attack.
Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.
Deliang
D
Shen
Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina, USA Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, North Carolina, USA.
Junnan
J
Tang
Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina, USA Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, North Carolina, USA.
Michael Taylor
MT
Hensley
Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
Taosheng
T
Li
Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Thomas George
TG
Caranasos
Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina, USA.
Tianxia
T
Zhang
Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China ke_cheng@ncsu.edu ke_cheng@unc.edu jyzhang@zzu.edu.cn.
Jinying
J
Zhang
Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina, USA Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, North Carolina, USA Cyrus Tang Hematology Center, Soochow University, Suzhou, Jiangshu, People's Republic of China ke_cheng@ncsu.edu ke_cheng@unc.edu jyzhang@zzu.edu.cn.
Ke
K
Cheng
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D004151:Dipeptides / Q000008:administration & dosage; D004195:Disease Models, Animal; D004452:Echocardiography; D005337:Fibrin / Q000008:administration & dosage; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D012038:Regeneration / Q000187:drug effects; D033581:Stem Cell Transplantation
D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D005337:Fibrin; D020782:Matrix Metalloproteinases
Cardiac stem cells; Heart repair; Matrix metalloproteinases; Platelet fibrin gel