Mohamed Amine Benadjaoud1, Frédéric Soysouvanh2, Georges Tarlet3, Vincent Paget3, Valérie Buard3, Henrique Santos de Andrade3, Ian Morilla3, Morgane Dos Santos4, Annaïg Bertho1, Bruno l'Homme4, Gaëtan Gruel4, Agnès François3, Michele Mondini5, Eric Deutsch6, Olivier Guipaud3, Fabien Milliat7. 1. Institute for Radiological Protection and Nuclear Safety (IRSN), Radiobiology of Medical Exposure Laboratory, Fontenay-aux-Roses; IRSN, Department of Radiobiology and Regenerative Medicine, Fontenay-aux-Roses. 2. Institute for Radiological Protection and Nuclear Safety (IRSN), Radiobiology of Medical Exposure Laboratory, Fontenay-aux-Roses; Sorbonne University, Doctoral College, Paris. 3. Institute for Radiological Protection and Nuclear Safety (IRSN), Radiobiology of Medical Exposure Laboratory, Fontenay-aux-Roses. 4. IRSN, Radiobiology of Accidental Exposure Laboratory, Fontenay-aux-Roses. 5. Gustave Roussy, Université Paris-Saclay, SIRIC SOCRATE, Villejuif; French National Institute of Health and Medical Research (INSERM), Villejuif; Univ Paris Sud, Université Paris-Saclay, Le Kremlin-Bicêtre; INSERM U1030 Gustave Roussy, Villejuif. 6. Gustave Roussy, Université Paris-Saclay, SIRIC SOCRATE, Villejuif; French National Institute of Health and Medical Research (INSERM), Villejuif; Univ Paris Sud, Université Paris-Saclay, Le Kremlin-Bicêtre; INSERM U1030 Gustave Roussy, Villejuif; Gustave Roussy, Université Paris-Saclay, Département de Radiothérapie, Villejuif, France. 7. Institute for Radiological Protection and Nuclear Safety (IRSN), Radiobiology of Medical Exposure Laboratory, Fontenay-aux-Roses. Electronic address: fabien.milliat@irsn.fr.
Abstract
PURPOSE: Radiation-induced cellular senescence is a double-edged sword, acting as both a tumor suppression process limiting tumor proliferation, and a crucial process contributing to normal tissue injury. Endothelial cells play a role in normal tissue injury after radiation therapy. Recently, a study observed an accumulation of senescent endothelial cells (ECs) around radiation-induced lung focal lesions following stereotactic radiation injury in mice. However, the effect of radiation on EC senescence remains unclear because it depends on dose and fractionation, and because the senescent phenotype is heterogeneous and dynamic. METHODS AND MATERIALS: Using a systems biology approach in vitro, we deciphered the dynamic senescence-associated transcriptional program induced by irradiation. RESULTS: Flow cytometry and single-cell RNA sequencing experiments revealed the heterogeneous senescent status of irradiated ECs and allowed to deciphered the molecular program involved in this status. We identified the Interleukin-1 signaling pathway as a key player in the radiation-induced premature senescence of ECs, as well as the endothelial-to-mesenchymal transition process, which shares strong hallmarks of senescence. CONCLUSIONS: Our work provides crucial information on the dynamics of the radiation-induced premature senescence process, the effect of the radiation dose, as well as the molecular program involved in the heterogeneous senescent status of ECs.
PURPOSE: Radiation-induced cellular senescence is a double-edged sword, acting as both a tumor suppression process limiting tumor proliferation, and a crucial process contributing to normal tissue injury. Endothelial cells play a role in normal tissue injury after radiation therapy. Recently, a study observed an accumulation of senescent endothelial cells (ECs) around radiation-induced lung focal lesions following stereotactic radiation injury in mice. However, the effect of radiation on EC senescence remains unclear because it depends on dose and fractionation, and because the senescent phenotype is heterogeneous and dynamic. METHODS AND MATERIALS: Using a systems biology approach in vitro, we deciphered the dynamic senescence-associated transcriptional program induced by irradiation. RESULTS: Flow cytometry and single-cell RNA sequencing experiments revealed the heterogeneous senescent status of irradiated ECs and allowed to deciphered the molecular program involved in this status. We identified the Interleukin-1 signaling pathway as a key player in the radiation-induced premature senescence of ECs, as well as the endothelial-to-mesenchymal transition process, which shares strong hallmarks of senescence. CONCLUSIONS: Our work provides crucial information on the dynamics of the radiation-induced premature senescence process, the effect of the radiation dose, as well as the molecular program involved in the heterogeneous senescent status of ECs.