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We thank Muriel Rhinn for help with procedures. We thank the mouse facility at the Mouse Clinical Institute (ICS), the Histology Facilities at the Centre for Genomic Regulation and the Institut de Genetique et de Biologie Moleculaire et Cellulaire/ICS, and the phenotyping platform at the ICS for excellent technical support. Work in the Keyes lab wasfunded in part by grants from the Spanish Ministry for Economy and Competitiveness (SAF2013-49082-P), La Fondation Recherche Medicale (FRM) (AJE20160635985), Fondation ARC (PJA20181208104), IDEX Attractivite-University of Strasbourg (IDEX2017), and La Fondation Schlumberger pour l'Education et la Recherche (FSER) (FSER 19-Year 2018), and ANR (ANR-19-CE13-0023-03). Work was also supported by grant ANR-10LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the frame program Investissements d'Avenir (ANR10-IDEX-0002-02). Weacknowledge the support of the Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme/Generalitat de Catalunya. Author contributions: B.R., M.P.C., andW.M.K. conceived and designed the study. B.R. performed most of the experiments. T.K.-M., A.M., J.-L.P., D.S.G., M.D., U.D.V., and E.P. performed additional experiments and techniques. H.J. performed histopathological analysis. B.R. and W.M.K. wrote the manuscript. M.P.C. and W.M.K. supervised the project and secured funding. All authors approved the manuscript.

Analysis of institutional authors

Ritschka, BAuthorMas, AAuthorDi Vicino, UAuthorCosma, MpAuthorKeyes, WmCorresponding Author

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July 6, 2020
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Article

The senotherapeutic drug ABT-737 disrupts aberrant p21 expression to restore liver regeneration in adult mice

Publicated to:Genes & Development. 34 (7-8): 489-494 - 2020-04-01 34(7-8), DOI: 10.1101/gad.332643.119

Authors: Ritschka, B; Knauer-Meyer, T; Goncalves, DS; Mas, A; Plassat, JL; Durik, M; Jacobs, H; Pedone, E; Di Vicino, U; Cosma, MP; Keyes, WM

Affiliations

Barcelona Inst Sci & Technol, CRG, Barcelona 08003, Spain - Author
CNRS, UMR7104, F-67404 Illkirch Graffenstaden, France - Author
IGBMC, F-67404 Illkirch Graffenstaden, France - Author
INSERM, U1258, F-67404 Illkirch Graffenstaden, France - Author
Inst Catalana Invest & Estudios Avanzados ICREA, Barcelona 08010, Spain - Author
Univ Strasbourg, F-67404 Illkirch Graffenstaden, France - Author
UPF, Barcelona 08003, Spain - Author
ViennaBioctr VBC, Res Inst Mol Pathol IMP, Campus Vienna Bioctr 1, A-1030 Vienna, Austria - Author
ViennaBioctr VBC, Res Inst Mol Pathol IMP, Campus Vienna Bioctr 1, A-1030 Vienna, AustriaIGBMC, F-67404 Illkirch Graffenstaden, France - Author
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Abstract

Young mammals possess a limited regenerative capacity in some tissues, which is lost upon maturation. We inves-tigated whether cellular senescence might play a role in such loss during liver regeneration. We found that fol- lowing partial hepatectomy, the senescence-associated p21, p16(Ink4a), genes and p19(Arf) become dynamically ex- pressed in different cell types when regenerative capacity decreases, but without a full senescent response. Howev-er, we show that treatment with a senescence-inhibiting drug improves regeneration, by disrupting aberrantly pro-longed p21 expression. This work suggests that senes-cence may initially develop from heterogeneous cellular responses, and that senotherapeutic drugs might be useful in promoting organ regeneration.

Keywords

abt-737agingcellsgene-expressionhepatocyteliver regenerationp16(ink4a)p16ink4ap21partial-hepatectomysenescencesenolytic4 [4 (4' chloro 2 biphenylylmethyl) 1 piperazinyl] n [4 [3 dimethylamino 1 (phenylthiomethyl)propylamino] 3 nitrobenzenesulfonyl]benzamideAbt-737AdultAgingAlanine aminotransferaseAnimalAnimal cellAnimal experimentAnimal modelAnimal tissueAnimalsArf proteinArticleAspartate aminotransferaseBiphenyl compoundsBiphenyl derivativeC57bl mouseCell agingCell cultureCell cycleCell functionCells, culturedCellular senescenceControlled studyCyclin dependent kinase inhibitor 1aCyclin dependent kinase inhibitor 2aCyclin-dependent kinase inhibitor p16Cyclin-dependent kinase inhibitor p21CytokineDrug effectDrug mechanismFemaleGene expressionGene expression regulationGeneticsHepatocyteHistologyImmunohistochemistryLipid storageLiverLiver cellLiver regenerationMaleMiceMice, inbred c57blModels, animalMouseNitrophenolNitrophenolsNonhumanP16ink4aP21Partial hepatectomyPhysiologyPiperazine derivativePiperazinesPriority journalProtein expressionProtein localizationProtein p19Protein p21RegenerationSenescenceSenolyticSenotherapeutic agentSulfonamideSulfonamidesUnclassified drugWestern blottingYoung adult

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Genes & Development due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2020, it was in position 9/176, thus managing to position itself as a Q1 (Primer Cuartil), in the category Genetics & Heredity. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 1.95. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 1.01 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 10.46 (source consulted: Dimensions Jul 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-07-25, the following number of citations:

  • WoS: 67
  • Scopus: 21
  • Europe PMC: 64

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-07-25:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 87.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 88 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 6.95.
  • The number of mentions on the social network X (formerly Twitter): 11 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Austria; France.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (RITSCHKA, BIRGIT) and Last Author (KEYES, BILL).

the author responsible for correspondence tasks has been KEYES, BILL.