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Lineage Tracing Evidence for In Vitro Dedifferentiation but Rare Proliferation of Mouse Pancreatic ß-Cells

¹ Department of Cellular Biochemistry and Human Genetics, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
² Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Address correspondence and reprint requests to Yuval Dor, Department of Cellular BiochemistryHuman Genetics, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel. E-mail dor{at}md.huji.ac.il

Abbreviations: BrdU, bromodeoxyuridine; HPAP, human placental alkaline phosphatase; JDRF, Juvenile Diabetes Research Foundation; PC1/3, prohormone convertase 1/3; YFP, yellow fluorescent protein

Understanding and manipulating pancreatic ß-cell proliferation is a major challenge for pancreas biology and diabetes therapy. Recent studies have raised the possibility that human ß-cells can undergo dedifferentiation and give rise to highly proliferative mesenchymal cells, which retain the potential to redifferentiate into ß-cells. To directly test whether cultured ß-cells dedifferentiate, we applied genetic lineage tracing in mice. Differentiated ß-cells were heritably labeled using the Cre-lox system, and their fate in culture was followed. We provide evidence that mouse ß-cells can undergo dedifferentiation in vitro into an insulin-, pdx1-, and glut2-negative state. However, dedifferentiated ß-cells only rarely proliferate under standard culture conditions and are eventually eliminated from cultures. Thus, the predominant mesenchymal cells seen in cultures of mouse islets are not of a ß-cell origin.

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