L-arginine from elder human mesenchymal stem cells induces angiogenesis and enhances therapeutic effects on ischemic heart diseases

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Abstract
BACKGROUND Mesenchymal stem cell (MSC)-based therapy may be a future treatment for myocardial infarction (MI). However, few studies have assessed the therapeutic efficacy of adipose tissue-derived MSCs (ADSCs) obtained from elderly patients in comparison to that of bone marrow-derived MSCs (BMSCs) from the same elderly patients. The metabolomics results revealed a significantly higher L-arginine excretion from aged ADSCs vs BMSCs in hypoxic conditions. This was hypothesized as the possible mechanism that ADSCs showed an improved angiogenic capacity and enhanced the therapeutic effect on ischemic heart diseases. AIM To investigate the role of L-arginine in enhancing angiogenesis and cardiac protection by comparing ADSCs and BMSCs in hypoxic conditions for MI therapy. METHODS Metabolomic profiling of supernatants from ADSCs and BMSCs under hypoxic conditions were performed. Then, arginine succinate lyase (ASL) overexpression and short hairpin RNA plasmid were prepared and transfected into BMSCs. Subsequently, in vitro wound healing and Matrigel tube formation assays were used to verify the proangiogenetic effects of ADSC positive control, BMSCs, BMSCs ASL short hairpin RNA, BMSCs ASL overexpressed, and BMSC negative control on cocultured human umbilical vein endothelial cells. All sample sizes, which were determined to meet the statistical requirements and be greater than 3, were established on the basis of previously established literature standards. The protein levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor, etc . were detected. In vivo , the five types of cells were transplanted into the infarcted area of MI rat models, and the therapeutic effects of the transplanted cells were evaluated by echocardiography on cardiac function and by Masson’s staining/terminal-deoxynucleotidyl transferase mediated nick end labeling assay/immunofluorescence detection on the infarcted area. RESULTS Metabolomic analysis showed that L-arginine was increased. Using ASL gene transfection, we upregulated the production of L-arginine in aged patient-derived BMSCs in vitro , which in turn enhanced mitogen activated protein kinase and VEGF receptor 2 protein expression, VEGF and basic fibroblast growth factor secretion, and inductive angiogenesis to levels comparable to donor-matched ADSCs. After the cell transplantation in vivo , the modified BMSCs as well as ADSCs exhibited decreased apoptotic cells, enhanced vessel formation, reduced scar size, and improved cardiac function in the MI rat model. The therapeutic efficacy decreased by inhibiting L-arginine synthesis. CONCLUSION L-arginine is important for inducing therapeutic angiogenesis for ADSCs and BMSCs in hypoxic conditions. ADSCs have higher L-arginine secretion, which leads to better angiogenesis induction and cardiac protection. ADSC transplantation is a promising autologous cell therapy strategy in the context of the present aging society.

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