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Effect of bone marrow mesenchymal stem cells-derived exosomes on diabetes-induced retinal injury: Implication of Wnt/ b-catenin signaling pathway - 10/09/22

Doi : 10.1016/j.biopha.2022.113554 
Nesrine Ebrahim a, b , Heba Elsayed Abd El-Halim a, Omayma Kamel Helal a, Nahla El-Eraky El-Azab a, Omnia A.M. Badr c , Amira Hassouna d , Hajir A.Al Saihati e , Nashwa Hassan Aborayah f , Hanan Tawfeek Emam f , Hend S. El-wakeel g , Mohammad Aljasir h , Mohamed El-Sherbiny i, j , Naglaa A.S. Sarg k , Gehan Ahmed Shaker l , Ola Mostafa a , Dina Sabry m, n , Marwa Abdel Kader Fouly o , Nicholas Robert Forsyth p , Nehal M. Elsherbiny q, r, , Rabab F. Salim s,
a Department of Histology and Cell Biology, Faculty of Medicine, Benha University, Egypt 
b Stem Cell Unit, Faculty of Medicine, Benha University, Egypt 
c Department of Genetics and Genetic Engineering, Faculty of Agriculture, Benha University, Egypt 
d School of Interprofessional Health Studies, Faculty of Health and Environmental Sciences, AUT University, Auckland, New Zealand 
e Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Hafr Albatin, Saudi Arabia 
f Department of Clinical Pharmacology, Faculty of Medicine, Benha University, Egypt 
g Department of Physiology, Faculty of Medicine, Benha University, Egypt 
h Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia 
i Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, P.O. Box 71666, Riyadh, 11597, Saudi Arabia 
j Department of Anatomy, Mansoura Faculty of Medicine, Mansoura University, Egypt 
k Department of Anatomy, Benha Faculty of Medicine, Benha University, Egypt 
l Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura, Egypt 
m Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Egypt 
n Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Badr University, Cairo 11562, Egypt 
o Research Institute of Ophthalmology, Cairo, Egypt 
p Guy Hilton Research Laboratories, School of Pharmacy and Bioengineering, Faculty of Medicine and Health Sciences, Keele University, Newcastle ST5 5BG, UK 
q Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia 
r Biochemistry department, Faculty of Pharmacy, Mansoura University, 35516, Mansoura, Egypt 
s Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Benha University, Egypt 

Corresponding author at: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia.Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of TabukTabukSaudi Arabia⁎⁎Corresponding author.

Abstract

Background

Diabetic retinopathy (DR) is a serious microvascular complication of diabetes mellitus. Mesenchymal stem cells are currently studied as therapeutic strategy for management of DR. Exosomes, considered as a promising cell-free therapy option, display biological functions similar to those of their parent cells. In retinal development, Wnt/b-catenin signaling provides key cues for functional progression. The present study aimed to evaluate the potential efficacy of bone marrow-derived mesenchymal stem cell-derived exosomes (BM-MSCs-Ex) in diabetes-induced retinal injury via modulation of the Wnt/ b-catenin signaling pathway.

Methods

Eighty-one rats were allocated into 6 groups (control, DR, DR + DKK1, DR + exosomes, DR + Wnt3a and DR + exosomes+Wnt3a). Evaluation of each group was via histopathological examination, assessment of gene and/or protein expression concerned with oxidative stress (SOD1, SOD2, Nox2, Nox4, iNOS), inflammation (TNF-α, ICAM-1, NF-κB) and angiogenesis (VEGF, VE-cadherin).

Results

Results demonstrated that exosomes blocked the wnt/b-catenin pathway in diabetic retina concomitant with significant reduction of features of DR as shown by downregulation of retinal oxidants, upregulation of antioxidant enzymes, suppression of retinal inflammatory and angiogenic markers. These results were further confirmed by histopathological results, fundus examination and optical coherence tomography. Additionally, exosomes ameliorative effects abrogated wnt3a-triggered retinal injury in DR.

Conclusion

Collectively, these data demonstrated that exosomes ameliorated diabetes-induced retinal injury via suppressing Wnt/ b-catenin signaling with subsequent reduction of oxidative stress, inflammation and angiogenesis.

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Abbreviations : Anti-VEGF, BM-MSCs-Ex, DM, DR, Fz, GCL, GFAP, GSK3b, IHC, ILM, INL, IPL, LRP5/6, NFL, OLM, ONL, PRL, RPE, STZ, TNF-α

Keywords : Diabetic retinopathy, Mesenchymal stem cells, Exosomes, Wnt/ b-catenin signaling, Oxidative stress, Angiogenesis


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