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Regeneration of Pancreatic Islets After Partial Pancreatectomy in Mice Does Not Involve the Reactivation of Neurogenin-3

¹ Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania
² Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
³ Division of Endocrinology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
⁴ Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania

Address correspondence and reprint requests to Doris A. Stoffers, MD, PhD, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Clinical Research Building 611 B, 415 Curie Blvd., Philadelphia, PA 19104. E-mail: stoffers{at}mail.med.upenn.edu. Or to Klaus H. Kaestner, PhD, Department of Genetics, University of Pennsylvania School of Medicine, Clinical Research Building 570, 415 Curie Blvd., Philadelphia, PA 19104. E-mail: kaestner{at}mail.med.upenn.edu

Key Words: EGFP, enhanced green fluorescent protein • Ngn3, neurogenin-3 • Ppx, partial pancreatectomy

Understanding the factors and mechanisms involved in ß-cell regeneration will guide therapeutic efforts to augment ß-cell mass in patients with diabetes. Neurogenin-3 (Ngn3) is a bHLH transcription factor that responds to Notch signaling and whose expression marks endocrine progenitors. During fetal development, all endocrine cells are derived from Ngn3⁺ precursors. Although expression of Ngn3 in the adult pancreas has not been reported, it has been suggested that islet regeneration in adult organisms recapitulates embryonic developmental pathways. Here, we investigated whether ß-cell regeneration in adult mice recapitulates the embryonic pathway involving Ngn3 activation. Despite full recovery of ß-cell mass after 50% partial pancreatectomy (Ppx) in BALB/c mice, no pancreatic Ngn3 immunoreactivity was detected, even when the ß-cell trophic glucagon-like peptide-1 receptor agonist exendin-4 was administered after the procedure. Even when we used the stable expression of enhanced green fluorescent protein (EGFP) in Ngn3^EGFP/+ mice to trace Ngn3 expression after Ppx, no pancreatic Ngn3 expression was detected. Although ectopic expression of Ngn3 can promote an endocrine transcriptional program in adult cells and may thus have therapeutic potential in the development of surrogate ß-cells, our studies indicate that a reactivation of endogenous Ngn3 expression is not required for adult ß-cell regeneration in vivo.

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