Can adipose stromal cells replace retinal pericytes in diabetic retinopathy? In vitro comparison of pro-angiogenic capacities of human ASC and retinal pericytes

Abstract

Background & Aim Pericyte dropout is a significant contribution to the microvascular complications leading to diabetic retinopathy (DR). The similarities with pericytes render adipose stromal cells (ASC) candidates to prevent vessel destabilization and control neoangiogenesis. In models of DR, ASC not only generate a cytoprotective and reparative environment by secretion of trophic factors acting on endothelial, neuronal and glial cells, but also engraft and integrate into the retina in a pericyte-like fashion. Concerns, however, are that AC may not withstand the hyperglycemic stress and may worsen DR by secretion of proangiogenic factors. Thus, we compared the angiogenic features of human ASC and retinal pericytes. Methods, Results & Conclusion We compared growth curves and marker expression of both cells. As angiogeneic features, we first assessed adhesion to endothelial extracellular matrix, modified by high-glucose. Next, we tested pro-angiogeneic properties of both cell types and their conditioned media on human retinal endothelial cells by means of vascular network formation. Further, we used whole genome microarrays to compare gene expression profiles. Based on multiplex cytokine results, inhibitors of certain cytokines used to assess their role in the angiogenic support. Although cells were not to be distinguished based on their phenotype, the pro-angiogenic activity was solely featured by ASC, whereas pericytes suppressed vascular network formation. Pericytes, in contrast to ASC, adhered and proliferated at reduced rates on high-glucose modified endothelial extracellular matrix. Differentially expressed genes clustered to cell adhesion and cell migration. Pericytes expressed predominantly genes related to vessel stabilisation, whereas ASC showed higher expression of genes related to angiogenesis. This was linked to cytokine secretion. In fact, VEGFR-2 was required for ASC angiogenic supportive capacities, whereas Ang-1 appeared not to be required for pericytes inhibitory action. Our results clearly document that the pro-angiogeneic activity discriminates ASC from retinal pericytes. Pericytes are marked by endothelial stabilizing properties whereas ASC rather show angiogenic supportive characteristics. These striking pro-angiogenic discrepancies prompts to investigate the ASC angiogeneic and potential pericyte replacement properties in more detail. Pericyte dropout is a significant contribution to the microvascular complications leading to diabetic retinopathy (DR). The similarities with pericytes render adipose stromal cells (ASC) candidates to prevent vessel destabilization and control neoangiogenesis. In models of DR, ASC not only generate a cytoprotective and reparative environment by secretion of trophic factors acting on endothelial, neuronal and glial cells, but also engraft and integrate into the retina in a pericyte-like fashion. Concerns, however, are that AC may not withstand the hyperglycemic stress and may worsen DR by secretion of proangiogenic factors. Thus, we compared the angiogenic features of human ASC and retinal pericytes. We compared growth curves and marker expression of both cells. As angiogeneic features, we first assessed adhesion to endothelial extracellular matrix, modified by high-glucose. Next, we tested pro-angiogeneic properties of both cell types and their conditioned media on human retinal endothelial cells by means of vascular network formation. Further, we used whole genome microarrays to compare gene expression profiles. Based on multiplex cytokine results, inhibitors of certain cytokines used to assess their role in the angiogenic support.