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BACKGROUND

News — 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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Core Tip: Adipose tissue-derived mesenchymal stem cells exhibited the advantages of angiogenesis compared to bone marrow-derived mesenchymal stem cells from elderly donors due to higher L-arginine secretion in serum-free and hypoxic conditions. In an animal model of MI, bone marrow-derived mesenchymal stem cells in which the arginine succinate lyase gene was integrated had a cardioprotective effect on angiogenesis. These results indicated that adipose tissue-derived mesenchymal stem cells from elderly patients with coronary heart disease and the introduction of L-arginine provide a promising strategy for stem cell therapy after MI.

• Citation: Li JZ, Zhan X, Sun HB, Chi C, Zhang GF, Liu DH, Zhang WX, Sun LH, Kang K. L-arginine from elder human mesenchymal stem cells induces angiogenesis and enhances therapeutic effects on ischemic heart diseases. World J Stem Cells 2025; 17(4): 103314
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