A critical role for iron import through the transferrin receptor in developing ß-cells

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 iPSCderived
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-TfrciKO,
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 maturationdependent
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 iPSCderived
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.