Epigenetic inhibitor zebularine activates ear pinna wound closure in the mouse

Piotr Sass , Paweł Sosnowski , Justyna Podolak-Popinigis , Bartosz Górnikiewicz , Jolanta Kamińska , Milena Deptuła , Ewa Nowicka , Anna Wardowska , Jarosław Ruczyński , Piotr Rekowski , Piotr Rogujski , Natalia Filipowicz , Alina Mieczkowska , Grażyna Peszyńska-Sularz , Łukasz Janus , Piotr Skowron , Artur Czupryn , Piotr Mucha , Arkadiusz Piotrowski , Sylwia Rodziewicz-Motowidło , Michał Pikuła , Paweł Sachadyn

Abstract

Background: Most studies on regenerative medicine focus on cell-based therapies and transplantations. Small-molecule therapeutics, though proved effective in different medical conditions, have not been extensively investigated in regenerative research. It is known that healing potential decreases with development and developmental changes are driven by epigenetic mechanisms, which suggests epigenetic repression of regenerative capacity. Methods: We applied zebularine, a nucleoside inhibitor of DNA methyltransferases, to stimulate the regenerative response in a model of ear pinna injury in mice. Findings: We observed the regeneration of complex tissue that was manifested as improved ear hole repair in mice that received intraperitoneal injections of zebularine. Six weeks after injury, the mean hole area decreased by 83.2 ± 9.4% in zebularine-treated and by 43.6 ± 15.4% in control mice (p b 10−30). Combined delivery of zebularine and retinoic acid potentiated and accelerated this effect, resulting in complete ear hole closurewithin three weeks after injury. We found a decrease in DNA methylation and transcriptional activation of neurodevelopmental and pluripotency genes in the regenerating tissues. Interpretation: This study is the first to demonstrate an effective induction of complex tissue regeneration in adult mammals using zebularine.Weshowed that the synergistic action of an epigenetic drug (zebularine) and a transcriptional activator (retinoic acid) could be effectively utilized to induce the regenerative response, thus delineating a novel pharmacological strategy for regeneration. The strategy was effective in the model of ear pinna regeneration in mice, but zebularine acts on different cell types, therefore, a similar approach can be tested in other tissues and organs.
Author Piotr Sass - [Politechnika Gdanska]
Piotr Sass,,
-
- Politechnika Gdanska
, Paweł Sosnowski - [Politechnika Gdanska]
Paweł Sosnowski,,
-
- Politechnika Gdanska
, Justyna Podolak-Popinigis - [Politechnika Gdanska]
Justyna Podolak-Popinigis,,
-
- Politechnika Gdanska
, Bartosz Górnikiewicz - [Politechnika Gdanska]
Bartosz Górnikiewicz,,
-
- Politechnika Gdanska
, Jolanta Kamińska - [Politechnika Gdanska]
Jolanta Kamińska,,
-
- Politechnika Gdanska
, Milena Deptuła - [Gdanski Uniwersytet Medyczny]
Milena Deptuła,,
-
- Gdanski Uniwersytet Medyczny
, Ewa Nowicka - [Gdanski Uniwersytet Medyczny]
Ewa Nowicka,,
-
- Gdanski Uniwersytet Medyczny
, Anna Wardowska - [Gdanski Uniwersytet Medyczny]
Anna Wardowska,,
-
- Gdanski Uniwersytet Medyczny
, Jarosław Ruczyński (FCh / DMB / LChBAC)
Jarosław Ruczyński,,
- Laboratory of Chemistry of Biologically Active Compounds
, Piotr Rekowski (FCh / DMB / LChBAC)
Piotr Rekowski,,
- Laboratory of Chemistry of Biologically Active Compounds
et al.`
Journal seriesEBioMedicine, ISSN , e-ISSN 2352-3964, (N/A 140 pkt)
Issue year2019
Vol46
Pages317-329
Publication size in sheets0.6
Keywords in EnglishRegeneration, epigenetics, ear pinna, mouse, zebularine, wound healing, regenerative medicine
ASJC Classification1300 General Biochemistry, Genetics and Molecular Biology; 2700 General Medicine
DOIDOI:10.1016/j.ebiom.2019.07.010
URL https://doi.org/10.1016/j.ebiom.2019.07.010
Languageen angielski
LicenseJournal (articles only); published final; Uznanie Autorstwa - Użycie Niekomercyjne - Bez utworów zależnych (CC-BY-NC-ND); with publication
Score (nominal)140
Score sourcejournalList
ScoreMinisterial score = 140.0, 06-12-2019, ArticleFromJournal
Publication indicators WoS Citations = 0; Scopus Citations = 0; Scopus SNIP (Source Normalised Impact per Paper): 2018 = 1.434; WoS Impact Factor: 2018 = 6.68 (2) - 2018=6.486 (5)
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