Determination of the therapeutic effect of the intravitreal administration of autologous adipose derived-mesenchymal stromal cells combined with anti-VEGF nanocarriers, in an animal model of induced retinal vein occlusion

Abstract

Background & Aim In recent years, anti-angiogenic therapeutic agents (anti-VEGF) have contributed to the treatment of retinal vein occlusion (RVO). At the same time, Mesenchymal Stromal Cells-mediated therapies (MSCs) are associated with secretory agents that protect the ganglion cells, limiting eye degeneration. The aim of the present study is to encapsulate anti-VEGF in thiolated chitosan nanocarriers (nanoThioCHI) and to determine the effect of their combination with rabbit adipose tissue MSCs (ASCs) in a MEK inhibitor-PD0325901-mediated induced animal model of RVO. Methods, Results & Conclusion Nanoparticles of ThioCHI were prepared by ionic gelation technique while polyclonal antibody-VEGF was inserted to the initial solution for anti-VEGF encapsulation. Their full characterization was followed using FT-IR, DSC and XRD. ASCs were isolated, cultured and characterized for their differentiation capacity and immunophenotypic characteristics. For the RVO induction New Zealand rabbits received intravitreal (iv) injections of PD0325901 dissolved in BSS (1 mg/eye) or BSS as control at a dose volume of 0.1 mL/eye and after 12days they were divided into 4 groups and received iv one of the followings: Group I:ASCs, Group II:nanoThioCHI, Group III: ASCs+nanoThioCHI, control Group IV: BSS only. Two weeks later the animals were sacrificed to determine the therapeutic efficacy of all the administered regimens. The retinal damage evaluated before and after the treatment via ophthalmic examinations, histological analysis, ELISA for secreted cytokines in peripheral blood and Q-PCR for the expression of related to the occlusion (VEGF, Apelin, Aqp4) and infflamatory (IL-6, Icam) genes. Limited retinal detachment, edema and retinal vasculature attenuation were observed in Groups I and III compared with the pathological symptoms of Group IV. As determined with H§E staining, Group IV presented a totally disorganized retinal structure in great contrast with the almost normal image, especially in case of Group III. Important reduction of the high secreted levels of inflammatory cytokines (TNF-a, IL-6) were quantified in Groups I and III while the expression of the RVO-related and inflammatory genes has been significantly decreased in ASCs+nanoThioCHI group (*p To sum up, we propose a stem cell-based therapy for RVO, accompanied by sustained and time-controlled release of anti-VEGF to combine the paracrine action of MSCs and the progressive reduction of neovascularization.