title: Drug-induced regeneration in adult mice.
abstract: Whereas amphibians regenerate lost appendages spontaneously, mammals generally form scars over the injury site through the process of wound repair. The MRL mouse strain is an exception among mammals because it shows a spontaneous regenerative healing trait and so can be used to investigate proregenerative interventions in mammals. We report that hypoxia-inducible factor 1α (HIF-1α) is a central molecule in the process of regeneration in adult MRL mice. The degradation of HIF-1α protein, which occurs under normoxic conditions, is mediated by prolyl hydroxylases (PHDs). We used the drug 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (1,4-DPCA), a PHD inhibitor, to stabilize constitutive expression of HIF-1α protein. A locally injectable hydrogel containing 1,4-DPCA was designed to achieve controlled delivery of the drug over 4 to 10 days. Subcutaneous injection of the 1,4-DPCA/hydrogel into Swiss Webster mice that do not show a regenerative phenotype increased stable expression of HIF-1α protein over 5 days, providing a functional measure of drug release in vivo. Multiple peripheral subcutaneous injections of the 1,4-DPCA/hydrogel over a 10-day period led to regenerative wound healing in Swiss Webster mice after ear hole punch injury. Increased expression of the HIF-1α protein may provide a starting point for future studies on regeneration in mammals.
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Iossif
authors.initials: I
authors.lastname: Strehin
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Khamilia
authors.initials: K
authors.lastname: Bedelbaeva
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Gourevitch
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Lise
authors.initials: L
authors.lastname: Clark
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: John
authors.initials: J
authors.lastname: Leferovich
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Messersmith
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA. heberkatz@limr.org.
authors.forename: Ellen
authors.initials: E
authors.lastname: Heber-Katz
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D012038:Regeneration
chemical_list: D002264:Carboxylic Acids; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit