Annexin A1 protein in retinogenesis and oxidative stress: Study in retinal organoids derived from human iPSCs

Abstract

Diseases that affect the retina have common triggers, such as oxidative stress, inflammation, and neuronal death in the retina. In the search for new potential therapeutic targets, retinal organoids emerge as a robust and technological platform that can aid in the discovery of new therapies. Annexin A1 (AnxA1) belongs to a family of proteins that bind to membrane phospholipids in a calcium-dependent manner. As a particular characteristic, AnxA1 is a protein with anti-inflammatory and pro-resolving activity, also participating in processes related to apoptosis and oxidative stress. In ocular diseases, the role of AnxA1 and the use of its mimetic peptide Ac2-26 as a pharmacological treatment have been investigated in different contexts such as uveitis, keratitis, glaucoma, and conjunctivitis, but little is known about its role in healthy retina and in conditions of damage. Studies conducted by our group in Brazil show that AnxA1 knockout animals present alterations in the retina's cone system and in ON-bipolar and OFF-bipolar cells. Additionally, in chronic diabetic retinopathy, AnxA1-/- animals show an exacerbated systemic inflammatory profile and increased retinal angiogenesis. Interestingly, the lack of AnxA1 in the retina is associated with negative regulation of gliosis. Thus, in the present project, we will evaluate the expression pattern of AnxA1 in in vitro retinogenesis, using retinal organoids derived from human induced pluripotent stem cells (iPSCs) at different stages of development. Furthermore, we will investigate the potential use of Ac2-26 in the response to oxidative stress in the retina in vitro using retinal organoids.