Rapid and synchronous chemical induction of replicative-like senescence via a small molecule inhibitor
Spiros Palikyras, Konstantinos Sofiadis, Athanasia Stavropoulou, Adi Danieli-Mackay, Vassiliki Varamogianni-Mamatsi, David Hörl, Simona Nasiscionyte, Yajie Zhu, Natasa Josipovic, Antonis Papadakis, Anne Zirkel, Aoife O’Connell, Gary Loughran, James Keane, Audrey Michel, Wolfgang Wagner, Andreas Beyer, Hartmann Harz, Heinrich Leonhardt, Grazvydas Lukinavicius, Christoforos Nikolaou, Argyris Papantonis
Cellular senescence is now acknowledged as a key contributor to organismal ageing and late-life disease. Although popular, the study of senescence in vitro can be complicated by the prolonged and asynchronous timing of cells committing to it and its paracrine effects. To address these issues, we repurposed the small molecule inhibitor inflachromene (ICM) to induce senescence to human primary cells. Within six days of treatment with ICM, senescence hallmarks, including the nuclear eviction of HMGB1 and -B2, are uniformly induced across IMR90 cell populations. By generating and comparing various high throughput datasets from ICM-induced and replicative senescence, we uncovered significant similarity of the two states. Notably though, ICM suppresses the proinflammatory secretome associated with senescence, thus alleviating most paracrine effects. In summary, ICM induces a senescence-like phenotype rapidly and synchronously thereby allowing the study of its core regulatory program without any confounding heterogeneity.