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

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Abstract

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 characterised. 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 highlight 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 allogeneic MSCs therapeutically to assist or repair the marrow microenvironment after HDC.

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Acknowledgements

We wish to express our gratitude to the doctors and nurses at the Southmead Hospital, Bristol, for bone marrow collections and to all patients who donated marrow samples. We would also like to thank the midwives at the Central Delivery Suite, Southmead Hospital, Bristol, for cord blood collections and the mothers who donated cord blood. This work was supported by a Ph.D. bursary from the University of the West of England, and also in part, by the funding provided by the Transplant Trust.

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  1. Centre for Research in Biomedicine, Faculty of Applied Sciences, University of the West of England, Bristol, UK

    Kevin Kemp, Ruth Morse, Kelly Sanders, Jill Hows & Craig Donaldson

  2. MS Group, Institute of Clinical Neurosciences, Frenchay Hospital, 1st Floor, The Burden Centre, Bristol, BS16 1JB, UK

    Kevin Kemp

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Kemp, K., Morse, R., Sanders, K. et al. Alkylating chemotherapeutic agents cyclophosphamide and melphalan cause functional injury to human bone marrow-derived mesenchymal stem cells. Ann Hematol 90, 777–789 (2011). https://doi.org/10.1007/s00277-010-1141-8

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