Intravitreal Administration Effect of Adipose-Derived Mesenchymal Stromal Cells Combined with Anti-VEGF Nanocarriers, in a Pharmaceutically Induced Animal Model of Retinal Vein Occlusion

Abstract

Antiangiogenic therapeutic agents (anti-VEGF) have contributed to the treatment of retinal vein occlusion (RVO) while mesenchymal stromal cell- (MSCs-) mediated therapies limit eye degeneration. The aim of the present study is to determine the effect of adipose-derived MSCs (ASCs) combination with nanocarriers of anti-VEGF in a pharmaceutically induced animal model of RVO. Nanoparticles (NPs) of thiolated chitosan (ThioCHI) with encapsulated anti-VEGF antibody were prepared. ASCs were isolated and genetically modified to secrete the green fluorescence GFP. Twenty-four New Zealand rabbits were divided into the I-IV equal following groups: ASCs, ASCs + nanoThioCHI-anti-VEGF, RVO, and control. For the RVO induction, groups I-III received intravitreal (iv) injections of MEK kinase inhibitor, PD0325901. Twelve days later, therapeutic regiments were administered at groups I-II while groups III-IV received BSS. Two weeks later, the retinal damage evaluated via detailed ophthalmic examinations, histological analysis of fixed retinal sections, ELISA for secreted cytokines in peripheral blood or vitreous fluid, and Q-PCR for the expression of related to the occlusion and inflammatory genes. Mild retinal edema and hemorrhages, limited retinal detachment, and vasculature attenuation were observed in groups I and II compared with the pathological symptoms of group III which presented a totally disorganized retinal structure, following of positive immunostaining for neovascularization and related to RVO markers. Important reduction of the high secreted levels of inflammatory cytokines was quantified in groups I and II vitreous fluid, while the expression of the RVO-related and inflammatory genes has been significantly decreased especially in group II. GFP+ ASCs, capable of being differentiated towards neural progenitors, detected in dissociated retina tissues of group II presenting their attachment to damaged area. Conclusively, a stem cell-based therapy for RVO is proposed, accompanied by sustained release of anti-VEGF, in order to combine the paracrine action of ASCs and the progressive reduction of neovascularization.

Autologous Adipose Tissue Stem Cell-Derived Terminally Differentiated Retinal Pigment Epithelium Monolayer on a Biocompatible Scaffold, to Restore Vision in Age-Related Macular Degeneration Patients

“…A probable cause is the trans-differentiation of injected MSCs into myofibroblast-like cells, which can induce fibrosis or proliferative vitreoretinopathy [25]. Complications, which are a significant issue of constant research, have additionally been attributed to the surgical procedure applied, number of administered MSCs, transplantation timing and the intrinsic mechanism of their in vivo action [42]. Therefore, for ocular or intraocular delivery of MSCs, it is imperative to follow more careful surgical procedures and more stricter control regarding the quality of MSC preparations [43].…”

Recent Advances of Adipose-Tissue-Derived Mesenchymal Stem Cell-Based Therapy for Retinal Diseases

“…Gounari et al evaluated the use of a stem-cell-based therapy for retinal vein occlusion (RVO) in a pharmaceutically induced animal model of RVO; the study investigated the effect of the paracrine action of ADSCs combined with anti-VEGF nanocarriers, which allowed for a sustained release of anti-VEGF, resulting in a progressive reduction in neovascularization [102].…”