Page 1 of 45 Diabetes
Yuchi et al.
ESTROGEN RECEPTOR α REGULATES BETA CELL FORMATION
DURING PANCREAS DEVELOPMENT AND FOLLOWING INJURY
Yixing Yuchi1,*, Ying Cai1,*, Bart Legein1,6, Sofie De Groef1, Gunter Leuckx1,
Violette Coppens1, Eva Van Overmeire2,3, Willem Staels1,4, Nico De Leu1,5, Geert Martens1, Jo A. Van Ginderachter2,3, Harry Heimberg1,# Mark Van de Casteele1,#
1Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium; 2Myeloid Cell Immunology Laboratory, VIB, 1040 Brussels, Belgium; 3Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, 1040 Brussels, Belgium; 4Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University Hospital and Department of Pediatrics and Genetics, Ghent University, Ghent, Belgium; 5Department of Endocrinology, UZ Brussel, 1090 Brussels, Belgium 6Current address: Experimental Vascular Pathology, Department of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands
*: equal contribution
#: equal contribution
(Total characters count: 33,957) Running Title: Estrogen regulates beta cell formation
Key words: beta cell/ development/ estrogen/ regeneration
Correspondence to: Harry Heimberg Diabetes Research Center Vrije Universiteit Brussel Laarbeeklaan 103 B1090 Brussels, Belgium Tel: 32 2 4774477 Fax: 32 2 4774472 e mail: [email protected]
Diabetes Publish Ahead of Print, published online May 26, 2015 Diabetes Page 2 of 45
Yuchi et al.
ABSTRACT
Identifying pathways for beta cell generation is essential for cell therapy in diabetes.
Here we investigate the potential of 17β estradiol (E2) and estrogen receptor (ER) signaling for stimulating beta cell generation during embryonic development and in severely injured adult pancreas. Estradiol concentration, ER activity and number of
ERα transcripts were enhanced in pancreas injured by partial duct ligation (PDL), along with nuclear localization of ERα 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 ERα was