Direct ionizing radiation and bystander effect in mouse mesenchymal stem cells

Abstract

Purpose: This study aimed to evaluate the radiation-induced direct and bystander (BYS) responses of mesenchymal stem cells (MSCs) and to characterize these cells radiobiologically.

Methods and materials: MSCs were irradiated (IR) and parameters related to DNA damage and cellular signaling were verified in a dose range from 0.5 to 15 Gy; also a transwell insert co-culture system was used to study medium-mediated BYS effects.

Results: The main effects on directly IR cells were seen at doses higher than 6 Gy: induction of cell death, cell cycle arrest, upregulation of p21, and alteration of redox status. Irrespective of a specific dose, induction of micronuclei formation, H2AX phosphorylation, and decreased Akt expression also occurred. Thus, mTOR expression, cell senescence, nitric oxide generation, and calcium levels, in general were not significantly modulated by radiation. Data from the linear-quadratic model showed a high alpha/beta ratio, which is consistent with a more exponential survival curve. BYS effects from the unirradiated MSCs placed into companion wells with the directly IR cells, were not observed.

Conclusions: The results can be interpreted as a positive outcome, meaning that the radiation damage is restricted to the directed IR MSCs not leading to off-target cell responses.

Keywords:

• Irradiation
• bystander effects
• mesenchymal stem cells
• DNA damage

Author contributions

Conceptualization, ANP, HRCS, and RAF; methodology, ANP, HRCS, KDH, AGFJ, CCD, AAH, ENM, PB, and EJPG; software, ANP and AGFJ; formal analysis, ANP, CCD, and AAH; investigation, ANP, CCD, and AAH; data curation, ANP; writing—original draft preparation, ANP, KDH, HRCS, and RAF; writing—review and editing, ANP, HRCS, and KDH; supervision, RAF and KDH; project administration, RAF and PB; funding acquisition, RAF.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by grants from the Fundação de Amparo à Pesquisa do Estado de São Paulo -FAPESP grants numbers: 2013/23285-0 and 2018/25813-8. Fock RA and Paredes-Gamero EJ are fellows of the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

Notes on contributors

Amanda Nogueira-Pedro

Amanda Nogueira-Pedro is a medical manager at pharmaceutical industry, and was a postdoc at the Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, Sao Paulo, Brazil and a research internship student at Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Helena Regina Comodo Segreto

Helena Regina Comodo Segreto, MD, PhD is Associate Professor at Department of Clinical and Experimental Oncology, Paulista School of Medicine, Federal University of São Paulo, Sao Paulo, Brazil.

Kathryn D. Held

Kathryn D Held, PhD is Associate Professor, Radiation Oncology, Harvard Medical School, Associate Radiation Biologist, Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Antonio Francisco Gentil Ferreira Junior

Antonio Francisco Gentil Ferreira Junior is a Scientist at the Institute of Technological Research, Sao Paulo, Brazil.

Carolina Carvalho Dias

Carolina Carvalho Dias is a PhD student at the Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, Sao Paulo, Brazil.

Araceli Aparecida Hastreiter

Araceli Aparecida Hastreiter is a PhD student at the Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, Sao Paulo, Brazil.

Edson Naoto Makiyama

Edson Naoto Makiyama is a research technician at the Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, Sao Paulo, Brazil.

Edgar Julian Paredes-Gamero

Edgar Julian Paredes-Gamero, PhD is a professor at the School of Pharmaceutical Sciences, Food and Nutrition, Federal University of Mato Grosso do Sul, Campo Grande, Brazil.

Primavera Borelli

Primavera Borelli, PhD is a full professor at the Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, Sao Paulo, Brazil.

Ricardo Ambrósio Fock

Ricardo Ambrósio Fock, PhD is Associate Professor and a group leader at the Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, Sao Paulo, Brazil.