title: Functional, persistent, and extended liver to pancreas transdifferentiation.
abstract: Pancreatic and duodenal homeobox gene-1 (PDX-1) regulates pancreas development during embryogenesis, whereas in the adult it controls beta-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 beta-cells in diabetics.
authors.affiliation: Endocrine Institute, Sheba Medical Center, Tel-Hashomer 52621, Israel.
authors.forename: Idit
authors.initials: I
authors.lastname: Ber
authors.forename: Keren
authors.initials: K
authors.lastname: Shternhall
authors.forename: Shira
authors.initials: S
authors.lastname: Perl
authors.forename: Zohar
authors.initials: Z
authors.lastname: Ohanuna
authors.forename: Iris
authors.initials: I
authors.lastname: Goldberg
authors.forename: Iris
authors.initials: I
authors.lastname: Barshack
authors.forename: Luna
authors.initials: L
authors.lastname: Benvenisti-Zarum
authors.forename: Irit
authors.initials: I
authors.lastname: Meivar-Levy
authors.forename: Sarah
authors.initials: S
authors.lastname: Ferber
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002460:Cell Line; D017931:DNA Primers; D018398:Homeodomain Proteins; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D010179:Pancreas / Q000166:cytology* / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D017931:DNA Primers; D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein