ESPE2024 Poster Category 2 Late Breaking (107 abstracts)
A critical role for iron import through the transferrin receptor in developing ß-cells.
Annelore Van Mulders 1 , Willem Staels 1 , Willems Lien 1 , Sophie Coenen 1 , Stephanie Bourgeois 1 , Yi Xiaoyan 2 , Tong Yue 2 , Gunter Leuckx 1 , Yves Heremans 1 , Eelco De Koning 3 , Francoise Carlotti 3 , Raphael Scharfmann 4 , Miriam Cnop 2 & Nico De Leu 1
1Vrije Universiteit Brussel, Brussels, Belgium. 2Université Libre de Bruxelles, Brussels, Belgium. 3LUMC, Leiden, Netherlands. 4INSERM, Paris, France
Introduction: The transferrin receptor (TFRC) is abundant on the surface of ß-cells compared to neighboring α- and ∂-cells, suggesting an important role of iron in ß-cell biology. The precise impact of iron on ß-cell development, function, and survival remains elusive. Here, we investigated the role of iron metabolism in mouse and human ß-cells through chemical and genetic modulation of iron supply.
Methods: To chemically modulate iron levels, mouse and human pancreatic islets, EndoC-ßH1 and human induced pluripotent stem cell (iPSC)-derived ß-cells were exposed to deferoxamine (DFO) or ferric citrate (FeCitr) for 24 hours to induce iron depletion or overload, respectively. Genetic iron deficiency was investigated using ß-cell-specific conditional (Ins1-Cre;Tfrcfl/fl or ß-Tfrc-KO) and inducible (Ins1-CreERT;Tfrcfl/fl or ß-Tfrc-iKO) Tfrc knockout mouse models, as well as an α-cell-specific (Gcg-Cre; Tfrcfl/fl) knockout.
Results: Chemical iron depletion increased TFRC expression in primary mouse and human islets, EndoC-ßH1 and iPSC-derived ß-cells, while iron overload decreased TFRC expression. Iron depletion in iPSC-derived pancreatic endocrine precursor cells (stage 5 of differentiation) resulted in significant cell death. In subsequent stages of differentiation, cells became more resistant to iron depletion, and the viability of long-cultured iPSC-derived ß-cell aggregates was unaffected. Genetic iron deficiency in mouse ß-cells (ß-Tfrc-KO) led to ß-cell loss and the onset of diabetes from 5 weeks of age onward, which iron injections could prevent. Induction of genetic iron deficiency in neonatal ß-cells (ß-Tfrc-iKO, induction at postnatal day 5) resulted in elevated blood glucose levels and impaired glucose tolerance, while no discernible effect was observed in adult ß-cells (ß-Tfrc-iKO, induction at 10 weeks). Genetic iron deficiency in α-cells did not impact their function or survival.
Conclusions: ß-cells demonstrate unique age and maturation-dependent responses to alterations in iron supply within the endocrine pancreas. TFRC-mediated iron import is crucial for ß-cell survival and function during ß-cell development, whereas this becomes dispensable in adulthood and mature stages of iPSC-derived ß-cell differentiation. These findings underscore an intricate relationship between iron metabolism and developmental ß-cell physiology, offering potential implications for improving the functional maturation of stem cell-derived ß-cells.
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