Mesenchymal stem cells show functional defect and decreased anti-cancer effect after exposure to chemotherapeutic drugs

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.Electronic supplementary materialThe online version of this article (10.1186/s12929-018-0407-7) contains supplementary material, which is available to authorized users.

Selective Cytotoxicity of a Novel Trp‐Rich Peptide against Lung Tumor Spheroids Encapsulated inside a 3D Microfluidic Device

“…Although there is a noticeable increase in the number of dead cells (>15%) in the MSC group exposed to 58 × 10 −6 m , it is less in comparison to the tumor spheroids exposed to the same ACP concentration (>75%, p < 0.005). Literature reports which have tested commercially available anticancer drugs against normal cells, including mesenchymal stem cells, [ 47 ] have reported significantly higher cell mortality. [ 25 ] For instance, Somaiah et al treated MSCs with the chemotherapeutic drugs cytarabine, daunorubicin or vincristine for 48 h and found that vincristine led to highest cell mortality (62.2% ± 2.4%) followed by cytarabine (54.2% ± 8.7%) and daunorubicin (40.3% ± 4.2%).…”

“…[ 25 ] For instance, Somaiah et al treated MSCs with the chemotherapeutic drugs cytarabine, daunorubicin or vincristine for 48 h and found that vincristine led to highest cell mortality (62.2% ± 2.4%) followed by cytarabine (54.2% ± 8.7%) and daunorubicin (40.3% ± 4.2%). [ 47 ]…”

Recent Advances on Drug-Loaded Mesenchymal Stem Cells With Anti-neoplastic Agents for Targeted Treatment of Cancer

“…Sorafenib causes 40% cell death at 465 ng/mL (Clavreul et al, 2017). Cytarabine, daunorubicin, and vincristine even in very low concentrations significantly induce apoptosis in hBM-MSCs (Nicolay et al, 2016b;Somaiah et al, 2018).…”

“…Because changes in the proliferation of MSCs has a pivotal role in drug loading, it is necessary to address the effect of chemotherapeutic drugs on cell cycle. It has been shown that treatment with paclitaxel (Pessina et al, 2011;Bonomi et al, 2017b;Petrella et al, 2017;Münz et al, 2018), gemcitabine (Bonomi et al, 2015b), pemetrexed (Petrella et al, 2017), bortezomib (Bonomi et al, 2017b), cytarabine, daunorubicin, and vincristine (Somaiah et al, 2018) inhibits cell proliferation of hBM-MSCs. Chemotherapeutic drugs decrease the proliferation of hAD-MSCs.…”

Angelica Sinensis Polysaccharides Ameliorate 5-Flourouracil-Induced Bone Marrow Stromal Cell Proliferation Inhibition Via Regulating Wnt/ β-Catenin Signaling

“…5-FU, widely used in highproliferative, tissue-derived cancers, particularly for colorectal cancer and breast cancer, exerts its anti-cancer effects through inhibition of thymidylate synthase (TS) and incorporation of its metabolites into RNA and DNA [10][11][12]. It was reported that the mechanism of stromal cells proliferation inhibition and apoptosis after 5-FU treatment is oxidative damage [13,14]. Our previous ndings have con rmed that following oxidative damage of BMSCs 5-FU may alter bioactive substance and cause stress-induced premature senescence (SIPS) of hematopoietic cells [15].…”