Protective Effects of Human Pericyte-like Adipose-Derived Mesenchymal Stem Cells on Human Retinal Endothelial Cells in an In Vitro Model of Diabetic Retinopathy: Evidence for Autologous Cell Therapy

Abstract

Diabetic retinopathy (DR) is characterized by morphologic and metabolic alterations in endothelial cells (ECs) and pericytes (PCs) of the blood–retinal barrier (BRB). The loss of interendothelial junctions, increased vascular permeability, microaneurysms, and finally, EC detachment are the main features of DR. In this scenario, a pivotal role is played by the extensive loss of PCs. Based on previous results, the aim of this study was to assess possible beneficial effects exerted by adipose mesenchymal stem cells (ASCs) and their pericyte-like differentiated phenotype (P-ASCs) on human retinal endothelial cells (HRECs) in high glucose conditions (25 mM glucose, HG). P-ASCs were more able to preserve BRB integrity than ASCs in terms of (a) increased transendothelial electrical resistance (TEER); (b) increased expression of adherens junction and tight junction proteins (VE-cadherin and ZO-1); (c) reduction in mRNA levels of inflammatory cytokines TNF-α, IL-1β, and MMP-9; (d) reduction in the angiogenic factor VEGF and in fibrotic TGF-β1. Moreover, P-ASCs counteracted the HG-induced activation of the pro-inflammatory phospho-ERK1/2/phospho-cPLA2/COX-2 pathway. Finally, crosstalk between HRECs and ASCs or P-ASCs based on the PDGF-B/PDGFR-β axis at the mRNA level is described herein. Thus, P-ASCs might be considered valuable candidates for therapeutic approaches aimed at countering BRB disruption in DR.

Molecular Mechanisms and Therapeutic Implications of Human Pericyte-like Adipose-Derived Mesenchymal Stem Cells in an In Vitro Model of Diabetic Retinopathy

“…Such an increase was more evident in P-ASC/HREC co-cultures, indicating their higher propensity to differentiate into PCs. These results confirm our previous data on ASC pericyte-like differentiation [54].…”

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

“…Adipose mesenchymal stem cells (ASCs) and their pericyte-like differentiated phenotype (P-ASCs) may also have a beneficial effect on human retinal endothelial cells (HRECs) in high-glucose conditions. P-ASCs might be considered strong candidates for therapeutic approaches aimed at countering blood-retinal barrier (BRB) disruption in DR, as suggested by Lupo et al [88]. The data presented herein provide evidence that ADSCs may serve as a promising therapeutic approach for DR [93].…”

Methylglyoxal Impairs the Pro-Angiogenic Ability of Mouse Adipose-Derived Stem Cells (mADSCs) via a Senescence-Associated Mechanism

“…Several studies demonstrate that ADSCs interact with ECs and promote their migration and recruitment for endothelialization [ 38 ]. Lupo et al have recently demonstrated that pericyte-like differentiated ADSCs preserve the blood-retinal barrier in an in vitro model of DR playing a positive effect on hRECs damaged by high glucose [ 39 ]. Moreover, Peng et al reported that the overexpression of the MGO-metabolizing enzyme Glo1, in ADSCs isolated from diabetic mice, is able to rescue the impaired ability of these cells to induce angiogenesis in human umbilical vein endothelial cells (HUVECs) [ 16 ].…”