p73alpha regulates the sensitivity of bone marrow mesenchymal stem cells to DNA damage agents

Abstract

Human bone marrow mesenchymal stem cells (MSCs) are important cell population located in bone marrow that are thought to have multiple functions in cell transplantation and gene therapy. Although in vitro experiments have demonstrated that hMSCs are resistant to apoptosis induction by DNA damage agents such as chemotherapeutic substances used in bone marrow transplantation, the molecular mechanism underlying remains unclear. p73 is highly similar to p53 and plays crucial roles in regulating DNA damage-induced apoptosis pathways. In this study, we investigated the role of p73 alpha in response to chemotherapeutic substances in cultured human bone marrow MSCs. Cellular chemosensitivity and DNA damage-induced apoptotic cell death were examined in the hMSCs with exogenously over-expressed p73 alpha. Our results showed that the expression of retrovirus-driven human p73 alpha could be successfully induced in hMSCs, the over-expression of ectopic p73 alpha resulted in a significant increase of cellular sensitivity to cisplatin. The increase of cellular apoptosis was attributed to enhanced chemosensitivity in p73 alpha infected cells. Moreover, immunoblot analysis indicated that the co-activation of pro-apoptotic factors Bax and p21 were observed in the p73 alpha infected cells after cisplatin treatment. In conclusion, our findings suggested that p73 alpha is an important determinant of cellular chemosensitivity in human bone marrow MSCs.