Sandra Ueberberg1, Andrea Tannapfel2, Peter Schenker3, Richard Viebahn3, Waldemar Uhl4, Stephan Schneider5, Juris J Meier6. 1. Diabetes Division, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, Bochum 44791, Germany. 2. Department of Pathology, Ruhr-University Bochum, Bürkle de la Camp-Platz 1, Bochum 44789, Germany. 3. Department of Surgery, Knappschaftskrankenhaus Bochum, Ruhr-University Bochum, In der Schornau 23-25, Bochum 44892, Germany. 4. Department of Surgery, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, Bochum 44791, Germany. 5. Department of Medicine II, St. Vinzenz Hospital, Merheimer Str. 221-223, Cologne 50733, Germany. 6. Diabetes Division, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, Bochum 44791, Germany. Electronic address: Juris.meier@rub.de.
Abstract
INTRODUCTION: The low frequency of beta-cell replication in the adult human pancreas limits beta-cell regeneration. A better understanding of the regulation of human beta-cell proliferation is crucial to develop therapeutic strategies aiming to enhance beta-cell mass. METHODS: To identify factors that control beta-cell proliferation, cell-cycle regulation was examined in human insulinomas as a model of increased beta-cell proliferation (n=11) and healthy pancreatic tissue from patients with benign pancreatic tumors (n=9). Tissue sections were co-stained for insulin and cell-cycle proteins. Transcript levels of selected cell-cycle factors in beta-cells were determined by qRT-PCR after performing laser-capture microdissection. RESULTS: The frequency of beta-cell replication was 3.74±0.92% in the insulinomas and 0.11±0.04% in controls (p=0.0016). p21 expression was higher in insulinomas (p=0.0058), and Rb expression was higher by trend (p=0.085), whereas p16 (p<0.0001), Cyclin C (p<0.0001), and p57 (p=0.018) expression levels were lower. The abundance of Cyclin D3 (p=0.62) and p27 (p=0.68) was not different between the groups. The reduced expression of p16 (p<0.0001) and p57 (p=0.012) in insulinomas and the unchanged expression of Cyclin D3 (p=0.77) and p27 (p=0.55) were confirmed using qRT-PCR. CONCLUSIONS: The expression of certain cell-cycle factors in beta-cells derived from insulinomas and healthy adults differs markedly. Targeting such differentially regulated cell-cycle proteins may evolve as a future strategy to enhance beta-cell regeneration.
INTRODUCTION: The low frequency of beta-cell replication in the adult human pancreas limits beta-cell regeneration. A better understanding of the regulation of human beta-cell proliferation is crucial to develop therapeutic strategies aiming to enhance beta-cell mass. METHODS: To identify factors that control beta-cell proliferation, cell-cycle regulation was examined in humaninsulinomas as a model of increased beta-cell proliferation (n=11) and healthy pancreatic tissue from patients with benign pancreatic tumors (n=9). Tissue sections were co-stained for insulin and cell-cycle proteins. Transcript levels of selected cell-cycle factors in beta-cells were determined by qRT-PCR after performing laser-capture microdissection. RESULTS: The frequency of beta-cell replication was 3.74±0.92% in the insulinomas and 0.11±0.04% in controls (p=0.0016). p21 expression was higher in insulinomas (p=0.0058), and Rb expression was higher by trend (p=0.085), whereas p16 (p<0.0001), Cyclin C (p<0.0001), and p57 (p=0.018) expression levels were lower. The abundance of Cyclin D3 (p=0.62) and p27 (p=0.68) was not different between the groups. The reduced expression of p16 (p<0.0001) and p57 (p=0.012) in insulinomas and the unchanged expression of Cyclin D3 (p=0.77) and p27 (p=0.55) were confirmed using qRT-PCR. CONCLUSIONS: The expression of certain cell-cycle factors in beta-cells derived from insulinomas and healthy adults differs markedly. Targeting such differentially regulated cell-cycle proteins may evolve as a future strategy to enhance beta-cell regeneration.
Authors: Natsuki Eguchi; Arvin John Toribio; Michael Alexander; Ivana Xu; David Lee Whaley; Luis F Hernandez; Donald Dafoe; Hirohito Ichii Journal: Biomedicines Date: 2022-02-17
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