Early impairment of paracrine and phenotypic features in resident cardiac mesenchymal stromal cells after thoracic radiotherapy

• Published in: International journal of molecular sciences Vol. 25; no. 5; p. 2873
• Main Authors: Picchio, Vittorio, Gaetani, Roberto, Pagano, Francesca, Derevyanchuk, Yuriy, Pagliarosi, Olivia, Floris, Erica, Cozzolino, Claudia, Bernava, Giacomo, Bordin, Antonella, Nunes Rocha, Filipe, Pereira, Ana, Almeida Ministro, Augusto Manuel, Pinto, Ana, De Falco, Elena, Serino, Gianpaolo, Massai, Diana, Tamarat, Radia, Pesce, Maurizio, Constantino Rosa Santos, Susana, Messina, Elisa, Chimenti, Isotta
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 01.03.2024; MDPI AG
• Subjects: Analysis; Animals; Cancer therapies; Cardiac fibrosis; Cardiac stromal cells; Cardiomyocytes; Cardiotoxicity; Cardiotoxicity - metabolism; Cell culture; Complications and side effects; Endothelial Cells - metabolism; Ethylenediaminetetraacetic acid; Fibroblasts; Heart Diseases - metabolism; Heart failure; Humans; Ischemia; Life Sciences; Mesenchymal Stem Cells - metabolism; Metabolism; Phenotype; Photographic industry; Radiation; Radiation Injuries - metabolism; Radiation therapy; Radiotherapy; Rats; Scientific equipment and supplies industry; Stem cells; United States; Massachusetts; Japan; radiotherapy; cardiac stromal cells; cardiotoxicity; radiation-induced heart disease; radiation-induced cardiomyopathy; cardiac fibrosis; cardiotoxicity radiotherapy radiation-induced cardiomyopathy radiation-induced heart disease cardiac fibrosis cardiac stromal cells
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25052873

© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Radiotherapy-induced cardiac toxicity and consequent diseases still represent potential severe late complications for many cancer survivors who undergo therapeutic thoracic irradiation. We aimed to assess the phenotypic and paracrine features of resident cardiac mesenchymal stromal cells (CMSCs) at early follow-up after the end of thoracic irradiation of the heart as an early sign and/or mechanism of cardiac toxicity anticipating late organ dysfunction. Resident CMSCs were isolated from a rat model of fractionated thoracic irradiation with accurate and clinically relevant heart dosimetry that developed delayed dose-dependent cardiac dysfunction after 1 year. Cells were isolated 6 and 12 weeks after the end of radiotherapy and fully characterized at the transcriptional, paracrine, and functional levels. CMSCs displayed several altered features in a dose- and time-dependent trend, with the most impaired characteristics observed in those exposed in situ to the highest radiation dose with time. In particular, altered features included impaired cell migration and 3D growth and a and significant association of transcriptomic data with GO terms related to altered cytokine and growth factor signaling. Indeed, the altered paracrine profile of CMSCs derived from the group at the highest dose at the 12-week follow-up gave significantly reduced angiogenic support to endothelial cells and polarized macrophages toward a pro-inflammatory profile. Data collected in a clinically relevant rat model of heart irradiation simulating thoracic radiotherapy suggest that early paracrine and transcriptional alterations of the cardiac stroma may represent a dose- and time-dependent biological substrate for the delayed cardiac dysfunction phenotype observed in vivo. This work was supported by the MEDIRAD project, which received funding from the Euratom research and training program 2014–2018 under grant agreement N. 755523. This work was also supported by grant # RM12117A805ED2FD from Sapienza University to IC. EDF is supported by grant “Progetto ECS 0000024 Rome Technopole, CUP B83C22002820006, PNRR Missione 4 Componente 2 Investimento 1.5”, funded by the European Union—Next GenerationEU.