The senotherapeutic drug ABT-737 disrupts aberrant p21 expression to restore liver regeneration in adult mice
- Birgit Ritschka1,2,3,4,5,8,
- Tania Knauer-Meyer1,2,3,4,
- Daniel Sampaio Gonçalves1,2,3,4,
- Alba Mas1,2,3,4,5,
- Jean-Luc Plassat1,2,3,4,
- Matej Durik1,2,3,4,
- Hugues Jacobs1,2,3,4,
- Elisa Pedone5,
- Umberto Di Vicino5,
- Maria Pia Cosma5,6,7 and
- William M. Keyes1,2,3,4,5,6
- 1Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch 67404, France;
- 2UMR7104, Centre National de la Recherche Scientifique (CNRS), Illkirch 67404, France;
- 3U1258, Institut National de la Santé et de la Recherche Médicale (INSERM), Illkirch 67404, France;
- 4Université de Strasbourg, Illkirch 67404, France;
- 5Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08003, Spain;
- 6Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain;
- 7Institución Catalana de Investigación y Estudios Avanzados (ICREA), Barcelona 08010, Spain
- Corresponding author: bill.keyes{at}igbmc.fr
Abstract
Young mammals possess a limited regenerative capacity in some tissues, which is lost upon maturation. We investigated whether cellular senescence might play a role in such loss during liver regeneration. We found that following partial hepatectomy, the senescence-associated genes p21, p16Ink4a, and p19Arf become dynamically expressed in different cell types when regenerative capacity decreases, but without a full senescent response. However, we show that treatment with a senescence-inhibiting drug improves regeneration, by disrupting aberrantly prolonged p21 expression. This work suggests that senescence may initially develop from heterogeneous cellular responses, and that senotherapeutic drugs might be useful in promoting organ regeneration.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.332643.119.
- Received September 11, 2019.
- Accepted February 4, 2020.
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