Estrogen Receptor α Regulates β-Cell Formation During Pancreas Development and Following Injury

• Published in: Diabetes (New York, N.Y.) Vol. 64; no. 9; pp. 3218 - 3228
• Main Authors: Yuchi, Yixing, Cai, Ying, Legein, Bart, De Groef, Sofie, Leuckx, Gunter, Coppens, Violette, Van Overmeire, Eva, Staels, Willem, De Leu, Nico, Martens, Geert, Van Ginderachter, Jo A, Heimberg, Harry, Van de Casteele, Mark
• Format: Journal Article
• Language: English
• Published: United States 01-09-2015
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cell Nucleus - metabolism; Cell Proliferation - genetics; Estradiol - metabolism; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Gene Expression Regulation, Developmental; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Mice; Mice, Knockout; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Pancreas - cytology; Pancreas - embryology; Pancreatic Ducts - injuries; RNA, Messenger - metabolism
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db14-1798

Identifying pathways for β-cell generation is essential for cell therapy in diabetes. We investigated the potential of 17β-estradiol (E2) and estrogen receptor (ER) signaling for stimulating β-cell generation during embryonic development and in the severely injured adult pancreas. E2 concentration, ER activity, and number of ERα transcripts were enhanced in the pancreas injured by partial duct ligation (PDL) along with nuclear localization of ERα in β-cells. PDL-induced proliferation of β-cells depended on aromatase activity. The activation of Neurogenin3 (Ngn3) gene expression and β-cell growth in PDL pancreas were impaired when ERα was turned off chemically or genetically (ERα(-/-)), whereas in situ delivery of E2 promoted β-cell formation. In the embryonic pancreas, β-cell replication, number of Ngn3(+) progenitor cells, and expression of key transcription factors of the endocrine lineage were decreased by ERα inactivation. The current study reveals that E2 and ERα signaling can drive β-cell replication and formation in mouse pancreas.