Abstract
BackgroundMesenchymal stem cells (MSC) are used for several therapeutic applications to improve the functions of bone, cardiac, nervous tissue as well as to facilitate the repopulation of hematopoietic stem cells. MSC give rise to the non-hematopoietic stromal cells of the bone marrow and are important for the maintenance of normal hematopoiesis. Chemotherapeutic drugs used for treatment of leukemia extensively damage the stromal cells and alter their gene expression profiles.MethodsWe determined the changes in adipogenic, osteogenic differentiation, phenotypic and gene expression in MSC during treatment with chemotherapeutic drugs cytarabine, daunorubicin and vincristine. We also tested anti-cancer effects of drug treated MSC on leukemia cells.ResultsTreatment with the chemotherapeutic drugs resulted in functional defects in MSC, leading to reduced proliferation, osteogenic and adipogenic differentiation. The drug treated MSC also showed decreased expression of cell surface receptors, and the changes in proliferation, phenotype and differentiation defect was partially reversible after withdrawing the drugs from the cells. The drug treated MSC showed increased expression of cytokines, IL6, FGF2 and TNFA but reduced levels of differentiation markers SOX9 and ACTC1. Drug treated MSC also contributed to reduced anti-cancer effects in leukemia cells.ConclusionsChemotherapeutic drug treatment altered the phenotype, osteogenic and adipogenic differentiation potential of MSC and modified the gene expression profile of the cells to render them more chemoprotective of the leukemic cells. Thus, additional therapeutic efforts to target the stromal cell population will help in preventing chemoresistance, disease relapse in leukemia and to maintain a healthy bone marrow stroma.
Highlights
Mesenchymal stem cells (MSC) are used for several therapeutic applications to improve the functions of bone, cardiac, nervous tissue as well as to facilitate the repopulation of hematopoietic stem cells
Chemotherapeutic drug treatment affects the morphology and proliferation of MSC In order to understand the effect of chemotherapeutic drugs used for leukemia treatment on the bone marrow MSC, the cells were treated with the chemotherapeutic agents CYT, DAU and VIN
MSC derived osteoblasts maintain the hematopoietic stem cells in the bone marrow [31], efficient osteoblastic differentiation of MSC treated with chemotherapeutic drug is important for tissue engineering applications as well as for the recovery of the normal hematopoiesis in the patient during remission
Summary
Mesenchymal stem cells (MSC) are used for several therapeutic applications to improve the functions of bone, cardiac, nervous tissue as well as to facilitate the repopulation of hematopoietic stem cells. When MSC are required for autologous transplantation to mediate tissue repair or regeneration, it is important to understand the changes sustained by the MSC due to exposure to the chemotherapeutic drugs. Another important aspect that must be understood is, whether the pre-exposure of MSC to chemotherapeutic drugs affect their ability to support the leukemic cells during chemotherapy since MSC have been shown to have functional aberrations and protect leukemia cells during chemotherapy [12, 13]. Chemotherapy treatment for leukemia is performed in several cycles and any change in the gene expression profile of the stromal cells which render them more supportive of the leukemic cells will result in an unfavorable outcome. Understanding the effect of chemotherapeutic drugs on the functional and gene expression properties of MSC will help in improving the treatment strategies for leukemia and to avoid relapse of the disease
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