Estrogen Receptor Alpha Regulates Beta-Cell Formation During Pancreas Development And Following Injury

Identifying pathways for beta-cell generation is essential for cell therapy in diabetes. We investigated the potential of 17 beta-estradiol (E-2) and estrogen receptor (ER) signaling for stimulating beta-cell generation during embryonic development and in the severely injured adult pancreas. E-2 concentration, ER activity, and number of ER alpha transcripts were enhanced in the pancreas injured by partial duct ligation (PDL) along with nuclear localization of ER alpha in beta-cells. PDL-induced proliferation of beta-cells depended on aromatase activity. The activation of Neurogenin3 (Ngn3) gene expression and beta-cell growth in PDL pancreas were impaired when ER was turned off chemically or genetically (ER alpha(-/-)), whereas in situ delivery of E-2 promoted beta-cell formation. In the embryonic pancreas, beta-cell replication, number of Ngn3(+) progenitor cells, and expression of key transcription factors of the endocrine lineage were decreased by ER alpha inactivation. The current study reveals that E-2 and ER alpha signaling can drive beta-cell replication and formation in mouse pancreas.