title: Overexpression of E2F3 promotes proliferation of functional human β cells without induction of apoptosis.
abstract: The mechanisms that control proliferation, or lack thereof, in adult human β cells are poorly understood. Controlled induction of proliferation could dramatically expand the clinical application of islet cell transplantation and represents an important component of regenerative approaches to a functional cure of diabetes. Adult human β cells are particularly resistant to common proliferative targets and often dedifferentiate during proliferation. Here we show that expression of the transcription factor E2F3 has a role in regulating β-cell quiescence and proliferation. We found human islets have virtually no expression of the pro-proliferative G 1/S transcription factors E2F1-3, but an abundance of inhibitory E2Fs 4-6. In proliferative human insulinomas, inhibitory E2Fs were absent, while E2F3 is expressed. Using this pattern as a "roadmap" for proliferation, we demonstrated that ectopic expression of nuclear E2F3 induced significant expansion of insulin-positive cells in both rat and human islets. These cells did not undergo apoptosis and retained their glucose-responsive insulin secretion, showing the ability to reverse diabetes in mice. Our results suggest that E2F4-6 may help maintain quiescence in human β cells and identify E2F3 as a novel target to induce proliferation of functional β cells. Refinement of this approach may increase the islets available for cell-based therapies and research and could provide important cues for understanding in vivo proliferation of β cells.
authors.affiliation: Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Rady
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Chen
authors.forename: Pilar
authors.initials: P
authors.lastname: Vaca
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Patrick
authors.initials: P
authors.lastname: Salmon
authors.forename: José
authors.initials: J
authors.lastname: Oberholzer
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D049109:Cell Proliferation; D050699:E2F3 Transcription Factor / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D046210:Microfluidic Analytical Techniques; D008856:Microscopy, Fluorescence; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D050699:E2F3 Transcription Factor; C098319:E2F3 protein, human
keywords: E2F; E2F3; beta-cell proliferation; beta-cell replication; cell cycle; insulin-secreting cells; insulinoma; islet transplant; type I diabetes
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