Therapeutic doses of doxorubicin induce premature senescence of human mesenchymal stem cells derived from menstrual blood, bone marrow and adipose tissue
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Doxorubicin (Dox) is an effective anticancer drug with known activity against a wide spectrum of malignancies, hematologic malignancies in particular. Despite extensive clinical use, the mechanisms of its side effects and negative action on normal cells remain under study. The aim of this study was to investigate the effect of Dox on cultured human mesenchymal stem cells (MSCs) derived from menstrual blood (eMSCs), bone marrow (BMSCs) and adipose tissue (AMSCs). Dox treatment in high doses decreased the survival of MSCs in a dose-dependent manner. Clinically relevant low doses of Dox induced premature senescence of eMSCs, BMSCs and AMSCs, but did not kill the cells. Dox caused cell cycle arrest and formation of γ-H2AX foci, and increased the number of SA-β-gal-positive cells. BMSCs entered premature senescence earlier than other MSCs. It has been reported that neural-like cells differentiated from MSCs of various origins are more sensitive to Dox than their parent cells. Dox-treated differentiated MSCs exhibited lower viability and earlier generation of γ-H2AX foci. Dox administration inhibited secretory activity in neural-like cells. These findings suggest that a clinically relevant Dox dose damages cultured MSCs, inducing their premature senescence. MSCs are more resistant to this damage than differentiated cells.
KeywordsDoxorubicin Mesenchymal stem cells Stress-induced premature senescence γ-H2AX foci
Mesenchymal stem cells
Bone marrow mesenchymal stem cells
Adipose mesenchymal stem cells
Endometrium from menstrual blood mesenchymal stem cells
Brain-derived neurotrophic factor
- SA- β-gal
Senescence-associated β galactosidase
Fluorescence-activated cell system
Enzyme-linked immunosorbent assay
Neuronal nuclear antigen
Glial fibrillary acidic protein
Basic fibroblast growth factor
Epidermal growth factor
Senescence-associated secretory phenotype
Stress-induced premature senescence
We thank Dr. Maxim Puzanov (Federal Almazov Medical Research Centre, Saint-Petersburg) for providing human bone marrow and adipose stem cell lines. We thank Dr. Irina Fridlyanskaya for critical revision of the manuscript. The work was supported by the Russian Science Foundation (Project 14-50-00068).
Compliance with ethical standards
The study was performed according to the Helsinki Declaration and approved by the “Ethics Committee of Federal Almazov Medical Research Centre”, Saint-Petersburg, Russia.
Conflict of interest
The authors declare that they have no conflict of interests.
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