Alkylating chemotherapeutic agents cyclophosphamide and melphalan cause functional injury to human bone marrow-derived mesenchymal stem cells

摘要

The adverse effects of melphalan and cyclophosphamide on hematopoietic stem cells are well known, however the effects on the mesenchymal stem cells (MSCs) residing in the bone marrow are less well characterized. Examining the effects of chemotherapeutic agents on patient MSCs in vivo is difficult due to variability in patients and differences in the drug combinations used, both of which could have implications on MSC function. As drugs are not commonly used as single agents during high dose chemotherapy (HDC) regimens there is a lack of data comparing the short or long term effects these drugs have on patients post treatment. To help address these problems the effects of the alkylating chemotherapeutic agents cyclophosphamide and melphalan on human bone marrow MSCs were evaluated in-vitro. Within this study the exposure of MSCs to the chemotherapeutic agents cyclophosphamide or melphalan had strong negative effects on MSC expansion and CD44 expression. In addition, changes were seen in the ability of MSCs to support hematopoietic cell migration and repopulation. These observations therefore implicate potential disadvantages in the use of autologous MSCs in chemotherapeutically pre-treated patients for future therapeutic strategies. Furthermore, this study suggests that if the damage caused by chemotherapeutic agents to marrow MSCs is substantial, it would be logical to use cultured MSCs therapeutically to assist or repair the marrow microenvironment after HDC.