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

Abstract

Identifying pathways for b-cell generation is essential for cell therapy in diabetes. We investigated the potential of 17b-estradiol (E 2 ) and estrogen receptor (ER) signaling for stimulating b-cell generation during embryonic development and in the severely injured adult pancreas. E 2 concentration, ER activity, and number of ERa transcripts were enhanced in the pancreas injured by partial duct ligation (PDL) along with nuclear localization of ERa in b-cells. PDL-induced proliferation of b-cells depended on aromatase activity. The activation of Neurogenin3 (Ngn3) gene expression and b-cell growth in PDL pancreas were impaired when ERa was turned off chemically or genetically (ERa 2/2 ), whereas in situ delivery of E 2 promoted b-cell formation. In the embryonic pancreas, b-cell replication, number of Ngn3 + progenitor cells, and expression of key transcription factors of the endocrine lineage were decreased by ERa inactivation. The current study reveals that E 2 and ERa signaling can drive b-cell replication and formation in mouse pancreas.Decreased functional b-cell mass is the major cause for hyperglycemia in diabetes. Restoration of the endogenous b-cell mass as a therapeutic strategy, however, requires a better understanding of signaling pathways that control b-cell growth and differentiation. Embryonic b-cells are generated by a developmental program executed through the timed action of a number of key transcription factors among which Neurogenin3 (Ngn3) is key for endocrine specification. Ngn3 + cells delaminate from pancreatic epithelium, are mitotically quiescent, and give rise to endocrine cells. Ngn3 cells appear maximally competent for driving b-cell formation at embryonic day (E) 14.5. Formed b-cells expand through self-replication, already evident at E18.5, and continue into early postnatal life (1). Also in adult mice with severely injured pancreas by partial duct ligation (PDL), Ngn3 + cells are generated near duct epithelium and can differentiate into b-cells (2). b-Cells are vastly generated through replication in PDL (3,4), but some derive from acinar (5) and duct (6) cells, apparently through an Ngn3 + stage (2,5) as in embryonic pancreas. How the numbers of Ngn3 + endocrine progenitors and replicating b-cells are controlled in the embryonic or mature pancreas is uncertain. Identifying factors that control these processes and manipulating them may be of therapeutic advantage. What is known is that 17b-estradiol (E 2 ) enhances b-cell survival and glycemic control in various animal models (7,8) by signaling through estrogen receptor (ER) a (8,9) and/or ERb (10).However, little is known about the importance of estrogen and ER signaling for b-cell proliferation and differentiation. So far, no in vivo effects on b-cell formation have been reported for the ER antagonist tamoxifen (TAM), although this compound is used to conditionally activate Cre recombinase activity (Cre ERT ) in genetic

Role of Sex Steroids in β Cell Function, Growth, and Survival

“…They can also derive from neogenesis via a NGN3+ stage [48]. Treatment with the ERα antagonist tamoxifen or genetic elimination of ERα in male mice similarly decreased NGN3 expression and β-cell proliferation in the PDL model, suggesting that ERα is involved in this process [49]. PDL increased E2 in the ligated portion of the pancreas and stimulated nuclear localization of ERα in β-cells (ERα is cytosolic β-cells under normal conditions).…”

“…PDL increased E2 in the ligated portion of the pancreas and stimulated nuclear localization of ERα in β-cells (ERα is cytosolic β-cells under normal conditions). ERα inhibition with tamoxifen in the embryonic pancreas, or its deletion as in the ERα-deficient mouse, also decreased NGN3 expression and NGN3+ progenitors at the end of gestation [49]. Thus, the generation of NGN3+ cells and the subsequent β-cell mass expansion in developing or injured mouse pancreas are both stimulated by ERα [49].…”

Extra-gonadal sites of estrogen biosynthesis and function

“…Estradiol increases insulin gene expression and insulin content in β-cells (59,79), increases β-cell proliferation during pancreatic development and recovery from injury (80), and prevents apoptosis of β-cells upon inflammatory insult (59) via ERα- and ERβ-mediated pathways.…”

The effect of selective estrogen receptor modulators on type 2 diabetes onset in women: Basic and clinical insights

“…For example, in wild-type female mice, tamoxifen reversed the protective effect of estradiol on preventing insulin-deficient diabetes induced by streptozotocin (STZ), suggesting that tamoxifen acts as an ER antagonist in pancreatic β cells and impairs pancreatic islet survival [20]. In addition, tamoxifen impairs embryonic and adult mouse β-cell proliferation by antagonism of ERα [21]. Treatment with tamoxifen or genetic elimination of ERα in male mice similarly decreased the expression of the endocrine specification factor Neurogenin3 (NGN3) and β-cell proliferation in the partial duct ligation (PDL) rodent model of β-cell expansion due to pancreatic injury.…”

“…Treatment with tamoxifen or genetic elimination of ERα in male mice similarly decreased the expression of the endocrine specification factor Neurogenin3 (NGN3) and β-cell proliferation in the partial duct ligation (PDL) rodent model of β-cell expansion due to pancreatic injury. Further, ERα inhibition with tamoxifen in the embryonic mouse pancreas, or its deletion as in the ERα-deficient mouse, also decreased NGN3 expression and NGN3+ progenitors at the end of gestation [21]. Thus, the generation of NGN3+ cells and the subsequent β-cell mass expansion in developing or injured mouse pancreas are both blocked by tamoxifen antagonizing ERα.…”