title: Presence of mesenchymal stem cells in human bone marrow after exposure to chemotherapy: evidence of resistance to apoptosis induction.
abstract: For various potential clinical applications, the use of autologous human MSCs (hMSCs) would be favorable. In vitro observations suggested that hMSCs are resistant for chemotherapeutic substances; however, no data exist on the characteristics of hMSCs from bone marrow (BM) of chemotherapeutically treated patients. Here, we analyzed the character of hMSCs derived from chemotherapy-exposed BM and the in vitro response of hMSCs to chemotherapeutic substances. Colony-forming units-fibroblast (CFU-Fs) were isolated from BM aspirates of patients after high-dose or standard chemotherapy and of donors with unaffected BM. CFU-Fs from chemotherapy-exposed and unaffected BM contained hMSCs with similar phenotype, proliferation capacity, and differentiation potential. No obvious influence of age, sex, or time since chemotherapy exposure on the presence and characteristics of hMSCs was observed. In vitro, hMSCs showed a significant resistance for cisplatin, vincristine, and etoposide compared with sensitive tumor cell lines, particularly at apoptosis-inducing doses. The phenotype and differentiation potential of hMSCs was not altered by genotoxic treatment under clinically relevant conditions in vitro. hMSCs 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 hMSCs to cisplatin, vincristine, and etoposide resulted in an increased p53 expression, independent of apoptosis induction. We conclude that hMSCs can be isolated from chemotherapy-exposed BM in sufficient number and quality for potential clinical applications in chemotherapeutically treated patients. Our data suggest that an elevated apoptotic threshold contributes not only to the persistence of hMSCs in the BM after chemotherapy but also to their lifelong presence in the adult BM.
authors.affiliation: Department of Medicine IV, Hematology/Oncology, Centre for Applied Medical and Human-Biological Research, Martin-Luther-University Halle-Wittenberg, Halle, Germany. lutz.mueller@medizin.uni-halle.de
authors.forename: Lutz P
authors.initials: LP
authors.lastname: Mueller
authors.forename: Jana
authors.initials: J
authors.lastname: Luetzkendorf
authors.forename: Thomas
authors.initials: T
authors.lastname: Mueller
authors.forename: Katrin
authors.initials: K
authors.lastname: Reichelt
authors.forename: Heike
authors.initials: H
authors.lastname: Simon
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Schmoll
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects*; D053453:Caspase 9 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D004351:Drug Resistance; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects*; D008875:Middle Aged; D009153:Mutagens; D010641:Phenotype; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D009153:Mutagens; D016159:Tumor Suppressor Protein p53; D053453:Caspase 9