Changes in the Functional Capacity of Marrow Stromal Cells after Autologous Bone Marrow Transplantation

Abstract

Marrow stromal cells were evaluated several months after autologous BMT for their capacity to support both normal hemopoiesis and secrete the main growth factors involved in its control, G-CSF, GM-CSF, IL-3 and SCF. Stromal layers (SL) were obtained by long-term marrow cultures (LTMC) established from 15 patients (9 with hematologic malignancies and 6 with solid tumors) 3 months after autologous BMT and were compared to pre-graft patients. After irradiation, both post-graft and pre-graft SL were recharged with the same inoculum of normal marrow cells. As compared to pre-graft values, CFU-GM production on post-graft SL was significantly increased during the first 2 weeks of culture whereas it was decreased from week 3 to week 8. These findings were only observed in patients with hematologic malignancies and not in patients with solid tumors. Growth factor secretion was evaluated by ELISA in the supernatants of unstimulated and IL-1-stimulated SL from 10 post-graft patients, 13 pre-graft patients and 5 normal controls. In any group of patients, IL-3 was undetectable either spontaneously or after IL-1-stimulation. As compared to controls, secretion by IL-1-stimulated SL was not different for GM-CSF in pre- and post-graft patients but tended to be decreased for G-CSF in post-graft patients. SCF secretion, which was not induced by IL-1, appeared dramatically decreased in both pre- and post-graft patients. The capacity of post-graft SL to support CFU-GM growth in LTMC was correlated at week 1 with G-CSF secretion and from week 3 to week 8 with SCF secretion. These results suggest that microenvironment remains qualitatively damaged several months after BMT involving a decreased capacity both to support early hemopoiesis and to secrete SCF, particularly in patients grafted for hemopoietic malignancies.

Presence of Mesenchymal Stem Cells in Human Bone Marrow After Exposure to Chemotherapy: Evidence of Resistance to Apoptosis Induction

“…We observed no differences in the proliferation capacity and mesodermal differentiation potential of hMSCs from chemotherapy‐exposed and unaffected BM. Our findings are in contrast to studies suggesting a quantitative and qualitative damage of BM stromal cells or hMSCs after hematopoietic stem cell transplantation [24, , , –28]. In contrast to our analysis, most of these studies did focus on the support of hematopoiesis by hMSCs.…”

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

“…Studies have also demonstrated that a recipient's stromal cells are damaged after bone marrow transplantation [10,11,13] or even from chemotherapeutic drugs alone [6,8].…”

“…Various studies to date have evaluated the toxic effects of HDC and demonstrated severe and irreversible damage on mature bone marrow stromal compartments in vivo and in vitro [5][6][7][8][9][10][11][12][13][14]. These effects are relevant not only in patients treated with HDC without allogeneic stem cells but also in recipients of allogeneic stem cell transplants in whom bone marrow stroma remains recipient in origin after the transplant [15][16][17].…”

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

“…Studies have also 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 also recently demonstrated a significant reduction in MSC expansion and MSC CD44 expression by MSCs derived from patients receiving HDC regimens for hematological malignancies, thus implicating potential disadvantages in the use of autologous MSCs in chemotherapeutically pre-treated patients for future therapeutic strategies [16].…”