The role of ferroptosis in pancreatic islet transplantation

Ferroptosis is an iron-dependent cell death, which is characterized by the formation of lethal lipid peroxidation and important in the pathogenesis of acute kidney failure. Ferroptosis can be inhibited by Ferrostatins (Fer1) and pharmaceutically induced by a molecule called Ras selective lethal 3 (RSL3). The intraportal transplantation of human pancreatic islets is a viable treatment strategy for patients with complicated type 1 diabetes. However, insufficient islet mass and functional impairment of islet grafts, due to cell death, are limiting the success of this therapy. Therefore, measures to increase the number of viable and functional islets in the isolation and transplantation process are of major interest.

Within this project, we aimed to investigate whether ferroptosis plays a relevant role in the context of pancreatic islet isolation and inhibition of this newly described pathway can improve islet quality and function. Ferroptosis is a genetically determined and regulated process that potentially results in the loss of islet function and promotes immunogenicity of the islets through necrotic debris.

For this project, we established an in vitro rodent model of isolated islets for investigation of islet viability, survival, and functional potency as well as morphological and Ferroptosis specific changes using immunohistochemistry following a treatment with RSL3 and Fer1 alone and in combination.

We could demonstrate that isolated islets are generally susceptible to pharmaceutically induced Ferroptosis and subsequent injury. This was indicated by pronounced expression of ACSL4, a pro-ferroptotic membrane protein and increased levels of MDA, the most prevalent byproducts of lipid peroxidation during oxidative stress, following RSL3 induction. This effect could be ameliorated by pretreatment with Fer1. In our model of rodent islet isolation, the impact of this pathway however was of minor relevance or could be compensated by its anti-oxidative capacity.

The prevention of cell death during islet isolation is an important measure to increase graft function after transplantation. Our hypothesis that the prevention of Ferroptosis due to treatment with Fer1 could possibly improve islet quality has been proven in our model of rodent islets when Ferroptosis was pharmaceutically induced. We could show evidence that the interference with the novel Ferroptosis pathways may contribute to improving islet quality prior to transplantation.