Using iron deficiency stress in plants as a tool for discovery of novel iron chelators for human use
Date
2024
Authors
Lane, Sarah
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Abstract
Iron is an essential micronutrient for life, but has harmful effects when dysregulated, especially when this leads to its accumulation in the body. Iron overload in humans contributes to the pathology of diseases like thalassemia, cancer and Parkinson’s Disease (PD). Treatments for iron overload can include chelation therapy to bind iron and remove it from tissues, but options authorized for clinical use are limited and can cause severe side effects. Plants are a good source of specialized, bioactive metabolites, and may be an untapped resource for novel iron chelators, as they produce these in roots to acquire environmental iron. This research uses a directed screening approach to find new chelators, taking advantage of plant biology by reducing iron in the plant growth environment to stimulate the production of iron-related metabolites, then testing them in a cell culture model of systemic iron overload.
Of three species explored in this research, Populus trichocarpa x P. deltoides (poplar) was shown to be the most promising candidate for iron chelator production. It had a widespread response to iron reduction, including increased production of sideretin, a known iron chelator, and trichocarpin, a salicinoid not previously associated with iron deficiencies. In phytochemical screening, it was mainly non-toxic and had dose-dependent antioxidant activity in unstressed THP-1 monocytic cells. When used in a model of systemic iron overload, it did not significantly decrease intracellular iron in these cells, but biological variation in source plants had a considerable effect on bioactivity. When a component of poplar root extract, chlorogenic acid, was used instead, it exerted a significant dose-dependent reduction of intracellular iron content. Modeling brain iron overload and chelation therapy in vitro is more challenging, and the final component of this research was to explore induced pluripotent stem cells as dopaminergic neurons in monolayer and 3D cell constructs for future modelling of chelation therapy. Patient-derived iPSC were successfully established in 3D culture as a stepping stone to investigating the use of iron chelators in 3D printed tissues. This work contributes to our understanding of iron acquisition strategies in plants, and presents novel ways to discover new therapeutic agents through plant-biology directed screening and innovative technology.
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Keywords
Iron metabolism, Plant biology, Cell biology, Iron overload, Iron chelators, Parkinson's Disease