Mesenchymal stem cells confer resistance to doxorubicin-induced cardiac senescence by inhibiting microRNA-34a.

Doxorubicin (DOXO) is a chemotherapeutic agent widely used in the treatment of various types of cancer. However, cardiotoxicity is a major side effect of DOXO therapy due to the ability of this compound to induce cardiac cellular senescence. It is well known that microRNA (miR)-34a serves a role in cardiac dysfunction and ageing, and that it is involved in several cellular processes associated with DOXO-induced cardiotoxicity. Furthermore, mesenchymal stem cell (MSC)-based therapies have been reported to modulate cellular senescence. In the present study, the Transwell system was used to co-culture H9c2 cells and MSCs, and cell proliferation and viability were assessed. The expression of senescence-related genes, p53 and p16, and telomere length were analyzed using reverse transcription-quantitative polymerase chain reaction (PCR), and the protein expression levels of situin 1 (SIRT1) were detected by western blotting. Additionally, telomerase activity of H9c2 was examined using the Telo TAGGG Telomerase PCR ELISA PLUS kit. The present study revealed that, in the presence of DOXO, H9c2 cells were in senescence, as characterized by a low proliferation rate, poor viability and a marked increase in the expression of p53 and p16. By contrast, when co-cultured with MSCs in the presence of DOXO, the proliferation and viability of H9c2 cells increased. Additionally, the expression of p53 and p16 decreased, and increased length of telomere and telomerase activity was also observed. Additionally, the mechanism underlying the anti-senescence function of MSCs was revealed to involve the miR-34a-SIRT1 axis, confirmed by overexpressing miR-34a using a miR-34a mimic or silencing SIRT1 using small interfering RNA, which abolished the anti-senescence effect of MSCs on DOXO-treated H9c2 cells. Taken together, the results of the present study suggest that MSCs may rejuvenate H9c2 cells from a state of DOXO-induced senescence by increasing SIRT1 expression, there by inhibiting miR-34a. Therefore, treatment with MSCs may have important therapeutic implications in the restoration of cardiotoxicity in patients with cancer undergoing treatment with DOXO.