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Adv Pharm Bull. 2023;13(2): 350-360.
doi: 10.34172/apb.2023.021
PMID: 37342375
PMCID: PMC10278222
  Abstract View: 937
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Research Article

Restoring the Angiogenic Capacity of the Human Diabetic Adipose-derived mesenchymal stem cells Primed with Deferoxamine as a Hypoxia Mimetic Agent: Role of HIF-1α

Raziye Tajali 1 ORCID logo, Akram Eidi 1, Hosein Ahmadi Tafti 2, Abdolreza Pazouki 3, Ali Mohammad Sharifi 4,5,6* ORCID logo

1 Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran.
2 Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center Hospital, Tehran University of Medical Sciences, Tehran, Iran.
3 Minimally Invasive Surgery Research Center, Iran University of Medical Sciences Tehran, Iran.
4 Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran.
5 Razi Drug Research Center, and Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
6 Tissue Engineering Group, (NOCERAL), Department of Orthopedics Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
*Corresponding Author: Tissue Engineering Group, (NOCERAL), Department of Orthopedics Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. Email Alisharifi@UM.edu.my
*Corresponding Author: Corresponding Author: Ali Mohammad Sharifi, Emails: sharifalim@gmail.com, sharifi.a@iums.ac.ir; , Email: Alisharifi@UM.edu.my

Abstract

Purpose: Insufficient angiogenesis is associated with serious diabetic complications. Recently, adipose-derived mesenchymal stem cells (ADScs) are known to be a promising tool causing therapeutic neovascularization. However, the overall therapeutic efficacy of these cells is impaired by diabetes. This study aims to investigate whether in vitro pharmacological priming with deferoxamine, a hypoxia mimetic agent, could restore the angiogenic potential of diabetic human ADSCs.

Methods: Diabetic human ADSCs were treated with deferoxamine and compared to normal and nontreated diabetic ADSCs for the expression of hypoxia inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2) and stromal cell-derived factor-1α (SDF-1α), at mRNA and protein levels, using qRT-PCR, western blotting and ELISA assay. Activities of matrix metalloproteinases (MMPs)-2 and -9 were measured using a gelatin zymography assay. Angiogenic potentials of conditioned media derived from normal, Deferoxamine treated, and non-treated ADSCs were determined by in vitro scratch assay and also three-dimensional tube formation assay.

Results: It is demonstrated that deferoxamine (150 and 300 μM) stabilized HIF-1α in primed diabetic ADSCs. At the concentrations used, deferoxamine did not show any cytotoxic effects. In deferoxamine treated ADSCs, expression of VEGF, SDF-1α, FGF-2 and the activity of MMP-2 and MMP-9 were significantly increased compared to nontreated ADSCs. Moreover, deferoxamine increased the paracrine effects of diabetic ADSCs in promoting endothelial cell migration and tube formation.

Conclusion: Deferoxamine might be an effective drug for pharmacological priming of diabetic ADSCs to enhance the expression of proangiogenic factors noted via HIF-1α accumulation. In addition, impaired angiogenic potential of conditioned medium derived from diabetic ADSCs was restored by deferoxamine.

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Submitted: 08 Sep 2021
Revision: 08 Jan 2022
Accepted: 10 Jan 2022
ePublished: 10 Jan 2022
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