Mesenchymal stem cells overexpressing integrin-linked kinase attenuate left ventricular remodeling and improve cardiac function after myocardial infarction.

In the present study, we investigated whether mesenchymal stem cells (MSCs) overexpressing integrin-linked kinase (ILK) might regulate ventricular remodeling and cardiac function in a porcine myocardial infarction model. ILK-modified MSCs (ILK-MSCs) (n = 8), MSCs (n = 8) or placebo (n = 8) were injected into peri-infarct myocardium 7 days after ligation of the left anterior descending coronary artery. ILK expression was confirmed by immunofluorescence, real-time PCR, Western blot analysis, and flow cytometry. In vitro assays indicated increased proliferation and reduced apoptosis of MSCs due to overexpression of ILK. Echocardiographic, single-photon emission computed tomography and positron emission tomography analyses demonstrated preserved cardiac function and myocardial perfusion. Reduced fibrosis, increased cardiomyocyte proliferation, and enhanced angiogenesis were observed in the ILK-MSC group. Reduced apoptosis, as demonstrated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling analysis, was also noted. In conclusion, ILK promotes MSC proliferation and suppresses apoptosis. ILK-MSC transplantation improves ventricular remodeling and cardiac function in pigs after MI. It is associated with increased angiogenesis, reduced apoptosis, and increased cardiomyocyte proliferation. This may represent a new approach to the treatment of post-infarct remodeling and subsequent heart failure.

Mesenchymal stem cells overexpressing integrin-linked kinase attenuate cardiac fibroblast proliferation and collagen synthesis through paracrine actions.

Mesenchymal stem cells (MSCs) transfected by integrin-linked kinase (ILK) transplantation may improve the function and compliance of the post-infarct cardiac ventricle. We investigated the effect of ILK-modified MSC contiditioned medium (ILK-MSC-CM) on the proliferation of cardiac fibroblasts (CFBs) and collagen synthesis in vitro and in vivo. Myocardial infarction (MI)-induced animals received mesenchymal stem cell conditioned medium (MSC-CM), ILK-MSC-CM, or complete medium alone, subepicardially. A group of animals with MI and no other former intervention served as controls. ILK-MSC-CM inhibited CFB proliferation, reduced the gene expression of type I (Col1a1) and type III collagen (Col3a1), tissue inhibitors of metalloproteinase­1 (TIMP-1) and ­2 (TIMP-2), α smooth muscle actin (α-SMA), and connective tissue growth factor (CTGF). It also increased the gene expression of matrix metalloproteinase­2 (MMP­2) and -9 (MMP­9), as measured by qRT-PCR. Four weeks after the left anterior descending (LAD) coronary artery ligation, echocardiographic analysis demonstrated preserved cardiac geometry and contractility in the ILK-MSC-CM treated animals. Decreased infarct size and reduced fibrosis were observed in the ILK-MSC-CM group. Overexpression of ILK regulates paracrine actions of MSCs, and ILK-MSC-CM attenuates CFB proliferation and collagen synthesis through paracrine actions in vitro and in vivo.