R Najafi1, Ali M Sharifi. 1. Tehran University of Medical Sciences, School of Medicine, Razi Drug Research Center, Department of Pharmacology, Tehran, Iran.
Abstract
OBJECTIVE: Today, cell therapy is considered a promising alternative in treatment of several diseases such as type 1 diabetes. Loss of transplanted stem cell and more importantly scarcity in the number of cells reaching to target tissue is a major obstacle in cell therapy. There is evidences showing that deferoxamine (DFO), an iron chelator, increases the mobilization and homing of progenitor cells through increasing the stability of hypoxia-inducible factor 1α (HIF-1α) protein. In this study, the effect of DFO on some factors involved in homing of bone marrow-derived mesenchymal stem cell was investigated, and the other objectives of this research were to determine whether DFO is able to increase migration and subsequent homing of mesenchymal stem cell (MSCs) both in vitro and in vivo in streptozotocin-diabetic rats. RESEARCH DESIGN AND METHODS: MSCs were treated by DFO in minimal essential medium α (αMEM) for 24 h. The expression and localization of HIF-1α were evaluated by western blotting and immunocytochemistry. The expression of C-X-C chemokine receptor type 4 (CXCR-4) and chemokine receptor 2 (CCR2) were assessed by western blotting and RT-PCR. The activity of matrix metalloproteinases (MMP) -2 and -9 were measured by gelatin zymography. Finally, in vitro migration of MSCs toward different concentrations of stromal cell-derived factor and monocyte chemotactic protein-1 were also evaluated. To demonstrate the homing of MSCs in vivo, DFO-treated chloromethyl-benzamidodialkylcarbocyanine-labeled MSCs were injected into the tail vein of rats, and the number of stained MSCs reaching to the pancreas were determined after 24 h. RESULTS: In DFO-treated MSCs, expression of HIF-1α (p < 0.001), CXCR4 (p < 0.001), CCR2 (p < 0.001), and the activity of MMP-2 (p < 0.01) and MMP-9 (p < 0.05) were significantly increased compared to control groups. Elevation of HIF-1α, upregulation of CXCR4/CCR2 and higher activity of MMP-2/MMP-9 in DFO-treated MSCs were reversed by 2-methoxyestradiol (2-ME; 5 μmol), a HIF-1α inhibitor. The in vitro migrations as well as in vivo homing of DFO-treated MSCs were also significantly higher than control groups (p < 0.05). CONCLUSIONS: Preconditioning of MSCs by DFO prior to transplantation could increase homing of MSCs through affecting some chemokine receptors as well as proteases involved and eventually improving the efficacy of cell therapy.
OBJECTIVE: Today, cell therapy is considered a promising alternative in treatment of several diseases such as type 1 diabetes. Loss of transplanted stem cell and more importantly scarcity in the number of cells reaching to target tissue is a major obstacle in cell therapy. There is evidences showing that deferoxamine (DFO), an iron chelator, increases the mobilization and homing of progenitor cells through increasing the stability of hypoxia-inducible factor 1α (HIF-1α) protein. In this study, the effect of DFO on some factors involved in homing of bone marrow-derived mesenchymal stem cell was investigated, and the other objectives of this research were to determine whether DFO is able to increase migration and subsequent homing of mesenchymal stem cell (MSCs) both in vitro and in vivo in streptozotocin-diabeticrats. RESEARCH DESIGN AND METHODS: MSCs were treated by DFO in minimal essential medium α (αMEM) for 24 h. The expression and localization of HIF-1α were evaluated by western blotting and immunocytochemistry. The expression of C-X-C chemokine receptor type 4 (CXCR-4) and chemokine receptor 2 (CCR2) were assessed by western blotting and RT-PCR. The activity of matrix metalloproteinases (MMP) -2 and -9 were measured by gelatin zymography. Finally, in vitro migration of MSCs toward different concentrations of stromal cell-derived factor and monocyte chemotactic protein-1 were also evaluated. To demonstrate the homing of MSCs in vivo, DFO-treated chloromethyl-benzamidodialkylcarbocyanine-labeled MSCs were injected into the tail vein of rats, and the number of stained MSCs reaching to the pancreas were determined after 24 h. RESULTS: In DFO-treated MSCs, expression of HIF-1α (p < 0.001), CXCR4 (p < 0.001), CCR2 (p < 0.001), and the activity of MMP-2 (p < 0.01) and MMP-9 (p < 0.05) were significantly increased compared to control groups. Elevation of HIF-1α, upregulation of CXCR4/CCR2 and higher activity of MMP-2/MMP-9 in DFO-treated MSCs were reversed by 2-methoxyestradiol (2-ME; 5 μmol), a HIF-1α inhibitor. The in vitro migrations as well as in vivo homing of DFO-treated MSCs were also significantly higher than control groups (p < 0.05). CONCLUSIONS: Preconditioning of MSCs by DFO prior to transplantation could increase homing of MSCs through affecting some chemokine receptors as well as proteases involved and eventually improving the efficacy of cell therapy.
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