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.

Chemotherapy-induced mesenchymal stem cell damage in patients with hematological malignancy

“…In contrast to our study, one focused on the effects of several chemotherapeutic agents used alone in vitro [30]; the other study did however present the effects of chemotherapy on MSCs in vivo but it did not focus on hematopoietic cell support. In addition, while their findings suggest that chemotherapy has no effect on MSC expansion and phenotype, there were several differences between our studies, for example differences in population sizes, experimental methods, times between last chemotherapy administration and bone marrow harvest, and most importantly chemotherapy dose and/or regimens used in the patient cohorts [42].…”

“…Thus, only the higher proliferating, less-affected MSC-derived stromal cultures were used in the comparative analysis between the high-dose and notreatment patient groups in these experiments. Two previous studies have suggested that MSCs are resistant to chemotherapeutic agents at clinically relevant doses [30,42]. In contrast to our study, one focused on the effects of several chemotherapeutic agents used alone in vitro [30]; the other study did however present the effects of chemotherapy on MSCs in vivo but it did not focus on hematopoietic cell support.…”

Human adipose tissue derived mesenchymal stem cells are resistant to several chemotherapeutic agents

“…Accordingly to previous reports, bone marrow derived MSCs are resistant to chemotherapeutic agents and irradiation (Chen et al 2006;Li et al 2004;Mueller et al 2006). In contrast, there are no studies in the literature regarding for the chemosensitivity of ADMSCs, this prompted us to analyze the acute and direct reaction of cultured ADMSCs exposed to single chemotherapeutic agent in vitro compared with that of TGCT cell line 2102EP which has been known of high sensitivity.…”

Modeling sarcomagenesis using multipotent mesenchymal stem cells

“…In addition, BMMSCs are resistant to chemotherapy-induced apoptosis [98][99][100] and contribute to generating drug resistance in tumor cells [95,101]. Likewise, several studies have evidenced that hMSCs are highly resistant to ionizing radiation [102].…”