Involvement of heparan sulfate and the proteoglycan Syndecan-1 in iron homeostasis of human induced pluripotent stem cells and derived hepatocytes

• Applicant: Dr. Charlotte Rossdam
• Subject Area: Cell Biology ; Biological and Biomimetic Chemistry
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 531278139

In the proposed project we will analyze the role of glycans that commonly decorate the outside of the cellular membrane in iron homeostasis. Iron homeostasis is finely regulated by a variety of different signaling pathways and its dysregulation is associated with several pathological conditions including anemias, neurodegenerative disorders, cardiac diseases, and cancer. A master regulator of iron homeostasis is the liver-derived peptide hormone hepcidin. Expression of hepcidin in the liver is regulated by heparan sulfate, a glycan that is attached to a distinct set of core proteins such as Syndecan-1. In this project, we would like to analyze the role of Syndecan-1 as a master regulator of hepcidin expression in stem cell-derived hepatocytes. Therefore, we will introduce a Syndecan-1 knockout in human induced pluripotent stem cells and differentiate these cells into hepatocytes. Hepcidin expression will be analyzed throughout the differentiation. Additionally, we will determine the impact of natural variation in heparan sulfate composition in human induced pluripotent stem cells and differentiated derivatives thereof on hepcidin regulation and iron metabolism. The structure of heparan sulfate is highly conserved and consists of repeating disaccharide units decorated with sulfate groups. However, there is inter-individual variation in its composition, length, and sulfation in different cells and tissues. This natural variation could result in differential susceptibility to iron associated disorders. Knowledge gained from this proposed project will help to understand the role of heparan sulfate and Syndecan-1 as a hepcidin regulator and a putative novel therapeutic target that can be used to treat iron overload disorders and iron-restricted anemias, which are the most common hematological diseases worldwide.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Privatdozent Philip Gordts, Ph.D.