Abstract
Stem cells are promising for the treatment of myocardial infarction (MI) and large animal models should be used to better understand the full spectrum of stem cell actions and preclinical evidences. In this study, bone marrow mesenchymal stem cells (BM-MSCs) were transplanted into swine heart ischemia model. To detect glucose metabolism in global left ventricular myocardium and regional myocardium, combined with assessment of cardiac function, positron emission tomography-computer tomography (PET-CT) and magnetic resonance imaging (MRI) were performed. To study the changes of glucose transporters and glucose metabolism-related enzymes and the signal transduction pathway, RT-PCR, Western-blot, and immunohistochemistry were carried out. Myocardium metabolic evaluation by PET-CT showed that mean signal intensity (MSI) increased in these segments at week 4 compared with that at week 1 after BM-MSCs transplantation. Moreover, MRI demonstrated significant function enhancement in BM-MSCs group. The gene expressions of glucose transporters (GLUT1, GLUT4), glucose metabolism-related enzymes phosphofructokinase (PFK), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH)) and 70-kDa ribosomal protein S6 kinase (p70s6k) in BM-MSCs injected areas were up-regulated at week 4 after BM-MSCs transplantation and this was confirmed by Western-blot and immunohistochemistry. In conclusions, BM-MSCs transplantation could improve cardiac function in swine MI model by activation of mTOR signal transduction pathway.
Highlights
The therapeutic mechanism of BM-MSCs transplantation has not been fully elucidated
The summed mean signal intensity (MSI) increased in the control group at week 4 compared with that of week 1 (1089.90 ± 24.47 vs. 1084.00 ± 21.15), and in the MSCs group, the summed MSI increased compared with 1st week (1075.50 ± 28.30 vs. 1013.50 ± 29.37)
The results of this study revealed that intramyocardial transplantation of BM-MSCs after AMI could improve cardiomyocytes’ glucose metabolism and cardiac function
Summary
The therapeutic mechanism of BM-MSCs transplantation has not been fully elucidated. It is considered that these cells possess pluripotent capabilities, including rapid proliferation, induction of angiogenesis, and differentiation into myogenic cells[4,5,6]. Low engraftment of transplanted cells could not explain the mechanism of the improved cardiac function[8]. The number of the survived stem cells settling down is limited in the lesions, but there is often a significant cardiac function improvement, which cannot be sufficiently explained by differentiation mechanisms[9,10]. Positron emission tomography (PET) imaging revealed that myocardial 2-Fluorine-18-Fluoro-2-deeoxy-D-glucose (18F-FDG) uptake increased after stem cells transplantation[12], indicating increased glucose metabolism in cardiomyocytes. Considering mTOR signal pathway controls protein synthesis in different levels by increasing the translation of certain mRNAs, we hypothesize here that the activation of mTOR signal transduction pathway by paracrine action of BM-MSCs after myocardial infarction, will further increase cardiomyocyte protein synthesis and glucose metabolism, and improve systolic function of heart
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