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J. Biol. Chem., Vol. 278, Issue 34, 31950-31957, August 22, 2003

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Functional, Persistent, and Extended Liver to Pancreas Transdifferentiation^*

Idit Ber   ¶, Keren Shternhall   ||, Shira Perl **, Zohar Ohanuna  ||, Iris Goldberg , Iris Barshack , Luna Benvenisti-Zarum  , Irit Meivar-Levy   and Sarah Ferber   

From the Endocrine Institute, Sheba Medical Center, Tel-Hashomer 52621, ^**Internal Medicine B, Meir Medical Center, Kfar-Saba 44281, Human Genetics, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 67978, ^||Life Science, Bar-Ilan University, Ramat-Gan 52900, and Pathology Institute, Sheba Medical Center, Tel-Hashomer 52621, Israel

Pancreatic and duodenal homeobox gene-1 (PDX-1) regulates pancreas development during embryogenesis, whereas in the adult it controls -cell function. Here we analyze whether PDX-1 functions as a pancreatic differentiation factor and a bona fide master regulator when ectopically expressed in mature fully differentiated liver in vivo. By ectopic and transient PDX-1 expression in liver in vivo, using the first generation recombinant adenoviruses, we demonstrate that PDX-1 induces in liver a wide repertoire of both exocrine and endocrine pancreatic gene expression. Moreover, PDX-1 induces its own expression (auto-induction), which in turn may explain the long lasting nature of the "liver to pancreas" transdifferentiation. Insulin as well glucagon-producing cells are mainly located in the proximity of hepatic central veins, possibly allowing direct hormone release into the bloodstream, without affecting normal hepatic function. Importantly, we demonstrate that hepatic insulin production triggered by Ad-CMV-PDX-1 recombinant adenovirus administration is functional and prevents streptozotocin-induced hyperglycemia in Balb/c mice even 8 months after the initial treatment. We conclude that PDX-1 plays an important instructive role in pancreas differentiation, not only from primitive gut endoderm but also from mature liver. Transconversion of liver to pancreas may serve as a novel approach for generating endocrine-pancreatic tissue that can replace malfunctioning -cells in diabetics.

Received for publication, March 26, 2003 , and in revised form, May 29, 2003.

^* The work was supported in part by Juvenile Diabetes Research Foundation Grant 1-2000-759 (to S. F.) and Post-doctoral Fellowship Grant 3-2002-230 (to I. M.-L.), Israel Science Foundation Grant ISF-380/00 (to S. F.), and in part by the Israel Ministry of Health-Mendel Chodowski fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ This work was performed in partial fulfillment of the requirements for a Ph.D. degree. Both authors contributed equally to this work.

To whom correspondence should be addressed. Tel.: 972-3-5303152; Fax: 972-3-5302083; E-mail: sferber{at}sheba.health.gov.il.

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