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

Abstract

Hematopoietic recovery after high-dose chemotherapy (HDC) in the treatment of hematological diseases may be slow and/or incomplete. This is generally attributed to progressive hematopoietic stem cell failure, although defective hematopoiesis may be in part due to poor stromal function. Chemotherapy is known to damage mature bone marrow stromal cells in vitro, but the extent to which marrow mesenchymal stem cells (MSCs) are damaged by HDC in vivo is largely unknown. To address this question, the phenotype and functional properties of marrow MSCs derived from untreated and chemotherapeutically treated patients with hematological malignancy were compared. This study demonstrates a significant reduction in MSC expansion and MSC CD44 expression by MSCs derived from patients receiving HDC regimens, thus implicating potential disadvantages in the use of autologous MSCs in chemotherapeutically pretreated patients for future therapeutic strategies. The clinical importance of these HDCinduced defects we have observed could be determined through prospective randomized trials of the effects of MSC cotransplantation on hematopoietic recovery in the setting of HDC with and without hematopoietic stem cell rescue.

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

“…Results indicated that exposure to these drugs did not cause any significant level of cell death to MSC cultures after 48 hours at the drug concentrations used. This resistance to apoptosis by cyclophosphamide is comparable to results seen by Li et al at identical drug concentrations [28], and may partially explain why MSCs can be harvested from bone-marrow derived from patients who have received prior high dose chemotherapy [16,43]. Although no significant loss of cell viability was observed, when investigating the expansion potential of MSCs post treatment, the mean expansion of untreated MSCs was over five times that seen of MSCs treated with melphalan after five passages.…”

“…Studies have demonstrated that a recipients stromal cells are damaged after bone marrow transplantation [6][7][8], or even from chemotherapeutic drugs alone [6][7][8][9][10][11][12][13][14][15]. We have recently demonstrated a significant reduction in MSC expansion and MSC CD44 expression by MSCs derived from patients receiving HDC regimens for hematological malignancies [16]. Examining the effects of chemotherapeutic agents on patient MSC 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.…”

“…The DNA damage response, involving sensory and effector proteins, is strongly tied with cellular proliferation, cell cycle arrest, cellular senescence and apoptosis [42,44]. Although investigating the exact mechanisms by which melphalan causes a decrease in MSC expansion would be desirable, it does demonstrate that chemotherapy disrupts the replicating ability of MSC, and corresponds with reductions in proliferative capacity of MSC harvested from patients who had received prior chemotherapy treatment [16]. This chemotherapy induced defect on proliferation is therefore a great concern as the ability/capacity for extensive proliferation and self-renewal is an essential property of a stem cell population.…”

“…Following exposure of MSC cultures to various chemotherapeutic agents structural abnormalities were evident with disruptions to the cell membrane morphology. MSC membrane surface expression of CD44 was also studied in response to the exposure of chemotherapeutic agents in-vitro as low CD44 levels seen on patients MSC after receiving high dose chemotherapy for hematological disorders [16]. CD44 is an adhesion molecule that plays a critical role in normal hematopoiesis [45][46], and it is the stromal microenvironment consisting of stromal cells and extra- or acting directly on the HSCs affecting their migration potential.…”

Enhancing the efficacy of mesenchymal stem cell therapy

“…Certain disease-causing genotypes may preclude therapeutic use of autologous MSCs due to the inherent genetic defects [24,25] . Even chemotherapy can induce MSC damage and reduce cell yields in patients with hematological malignancy [26] . Thus, the use of allogeneic MSCs from healthy donors is gaining acceptance.…”