Presence of mesenchymal stem cells in human bone marrow after exposure to chemotherapy - evidence of resistance to apoptosis-induction

¹ Department of Medicine IV - Hematology/Oncology, Centre for applied medical and human-biological Research (ZAMED), Martin-Luther-University Halle-Wittenberg, Germany

^* To whom correspondence should be addressed. E-mail: lutz.mueller{at}medizin.uni-halle.de.

	Abstract

For various potential clinical applications the use of autologous human mesenchymal stem cells (hMSC) would be favorable. In-vitro-observations suggested that hMSC are resistant for chemotherapeutic substances, however no data exist on the characteristics of hMSC from bone marrow (BM) of chemotherapeutically treated patients. Here, we analyzed the character of hMSC derived from chemotherapy-exposed BM and the in-vitro-response of hMSC to chemotherapeutic substances. Colony-forming-units-fibroblast (CFU-F) were isolated from BM-aspirates of patients after high-dose- or standard-chemotherapy and of donors with unaffected BM. CFU-F from chemotherapy-exposed and unaffected BM contained hMSC with similar phenotype, proliferation capacity and differentiation potential. No obvious influence of age, gender and time since chemotherapy-exposure on the presence and characteristics of hMSC was observed. In vitro, hMSC showed a significant resistance for cisplatin, vincristine and etoposide compared to sensitive tumor cell lines, particularly at apoptosis-inducing doses. The phenotype and differentiation potential of hMSC was not altered by genotoxic treatment at clinically relevant conditions in vitro. hMSC showed an elevated threshold for cisplatin-induced apoptosis which was characterized by a lack of caspase-9 activity in apoptotic cells. In-vitro-exposure of hMSC to cisplatin, vincristine and etoposide resulted in an increased p53-expression, independent of apoptosis-induction. We conclude that hMSC can be isolated from chemotherapy-exposed BM in sufficient number and quality for potential clinical applications in chemotherapeutically treated patients. Our data suggests, that an elevated apoptotic threshold contributes not only to the persistence of hMSC in the BM after chemotherapy but also to their life-long presence in the adult BM.