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Original Article
Regulated and Reversible Induction of Adult Human β-Cell Replication
Karen K. Takane, Jeffery W. Kleinberger, Fatimah G. Salim, Nathalie M. Fiaschi-Taesch and Andrew F. Stewart
Diabetes 2011 Dec; DB_110580. https://doi.org/10.2337/db11-0580
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Abstract

Induction of proliferation in adult human β-cells is challenging. It can be accomplished by introduction of cell cycle molecules such as cyclin-dependent kinase 6 (cdk6) and cyclin D1, but their continuous overexpression raises oncogenic concerns. We attempted to mimic normal, transient, perinatal human β-cell proliferation by delivering these molecules in a regulated and reversible manner. Adult cadaveric islets were transduced with doxycycline (Dox)-inducible adenoviruses expressing cdk6 or cyclin D1. End points were cdk6/cyclin D1 expression and human β-cell proliferation, survival, and function. Increasing doses of Dox led to marked dose- and time-related increases in cdk6 and cyclin D1, accompanied by a 20-fold increase in β-cell proliferation. Notably, Dox withdrawal resulted in a reversal of both cdk6 and cyclin D1 expression as well as β-cell proliferation. Re-exposure to Dox reinduced both cdk/cyclin expression and proliferation. β-Cell function and survival were not adversely affected. The adenoviral tetracycline (tet)-on system has not been used previously to drive human β-cell proliferation. Human β-cells can be induced to proliferate or arrest in a regulated, reversible manner, temporally and quantitatively mimicking the transient perinatal physiological proliferation that occurs in human β-cells.

  • Received May 2, 2011.
  • Accepted November 8, 2011.
  • © 2012 by the American Diabetes Association.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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Diabetes: 67 (5)

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May 2018
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Regulated and Reversible Induction of Adult Human β-Cell Replication
Karen K. Takane, Jeffery W. Kleinberger, Fatimah G. Salim, Nathalie M. Fiaschi-Taesch, Andrew F. Stewart
Diabetes Dec 2011, DB_110580; DOI: 10.2337/db11-0580

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Regulated and Reversible Induction of Adult Human β-Cell Replication
Karen K. Takane, Jeffery W. Kleinberger, Fatimah G. Salim, Nathalie M. Fiaschi-Taesch, Andrew F. Stewart
Diabetes Dec 2011, DB_110580; DOI: 10.2337/db11-0580
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