TGF-β1 and CXCL12 modulate proliferation and chemotherapy sensitivity of acute myeloid leukemia cells co-cultured with multipotent mesenchymal stromal cells

Schelker, Roland Christian; Iberl, Sabine; Müller, G.; Hart, Christina; Herr, Wolfgang; Grassinger, Jochen

doi:10.1080/10245332.2017.1402455

Cited by 29 publications

(32 citation statements)

References 30 publications

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“…Nevertheless, it has been demonstrated that the activation of TGF‐β‐Smad3 signaling reduces acute myeloid leukemia cells proliferation by causing cell cycle arrest at G 1 phase . Moreover, TGF‐β1 inhibition enhances acute myeloid cell proliferation in co‐culture with BM‐MSC .…”

Section: Discussionmentioning

confidence: 99%

Hydroxyurea‐induced senescent peripheral blood mesenchymal stromal cells inhibit bystander cell proliferation of JAK2V617F‐positive human erythroleukemia cells

et al. 2019

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Hydroxyurea (HU) is a nonalkylating antineoplastic agent used in the treatment of hematological malignancies. HU is a DNA replication stress inducer, and as such, it may induce a premature senescence‐like cell phenotype; however, its repercussion on bystander cell proliferation has not been revealed so far. Our results indicate that HU strongly inhibited peripheral blood mesenchymal stromal cells (PBMSC) proliferation by cell cycle arrest in S phase, and that, consequently, PBMSC acquire senescence‐related phenotypical changes. HU‐treated PBMSC display increased senescence‐associated β‐galactosidase levels and p16INK4 expression, as well as DNA damage response and genotoxic effects, evidenced by expression of γH2A.X and micronuclei. Moreover, HU‐induced PBMSC senescence is mediated by increased reactive oxygen species (ROS) levels, as demonstrated by the inhibition of senescence markers in the presence of ROS scavenger N‐acetylcysteine and NADPH oxidase inhibitor Apocynin. To determine the HU‐induced bystander effect, we used the JAK2V617F‐positive human erythroleukemia 92.1.7 (HEL) cells. Co‐culture with HU‐induced senescent PBMSC (HU‐S‐PBMSC) strongly inhibited bystander HEL cell proliferation, and this effect is mediated by both ROS and transforming growth factor (TGF)‐β expression. Besides induction of premature senescence, HU educates PBMSC toward an inhibitory phenotype of HEL cell proliferation. Finally, our study contributes to the understanding of the role of HU‐induced PBMSC senescence as a potential adjuvant in hematological malignancy therapies.

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Section: Discussionmentioning

confidence: 99%

Hydroxyurea‐induced senescent peripheral blood mesenchymal stromal cells inhibit bystander cell proliferation of JAK2V617F‐positive human erythroleukemia cells

et al. 2019

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“…CXCR4 and SDF-1 blockades in animal models culminates in a remarkable decrease in the migration potential and the migration rate of transplanted stem cells to sites of demyelination, suggesting that the SDF-1/CXCR4 signaling pathway is critical for effective stem cell therapy [62]. Moreover, simultaneous blocking of both CXCR4 and transforming growth factor (TGF)-β receptor demonstrated that CXCR4 is necessary for colonization of MSCs in tumors, differentiation to myofibroblasts, and MSC survival [63,64]. MSCs express several chemokine receptors, including CXCR1, CXCR3, CXCR4, CXCR5, CXCR6, CCR1, CCR2, CCR3, CCR4, CCR5, and CCR9 [65].…”

Section: Colonization and Migration Of Mscsmentioning

confidence: 99%

The Role of Mesenchymal Stem Cells in Atherosclerosis: Prospects for Therapy via the Modulation of Inflammatory Milieu

Gorabi

Banach

Reiner

et al. 2019

JCM

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Atherosclerosis is a chronic, inflammatory disease that mainly affects the arterial intima. The disease is more prevalent in middle-age and older individuals with one or more cardiovascular risk factors, including dyslipidemia, hypertension, diabetes, smoking, obesity, and others. The beginning and development of atherosclerosis has been associated with several immune components, including infiltration of inflammatory cells, monocyte/macrophage-derived foam cells, and inflammatory cytokines and chemokines. Mesenchymal stem cells (MSCs) originate from several tissue sources of the body and have self-renewal and multipotent differentiation characteristics. They also have immunomodulatory and anti-inflammatory properties. Recently, it was shown that MSCs have a regulatory role in plasma lipid levels. In addition, MSCs have shown to have promising potential in terms of treatment strategies for several diseases, including those with an inflammatory component. In this regard, transplantation of MSCs to patients with atherosclerosis has been proposed as a novel strategy in the treatment of this disease. In this review, we summarize the current advancements regarding MSCs for the treatment of atherosclerosis.

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“…As the interaction of leukemia cells with bone marrow stromal cells has impact on their biology and response to therapy and can modify the phenotype of stromal cells , it is of particular importance to verify the drugs efficiency in a bone marrow mimicking conditions. Most of the co‐culture studies concentrate on the stroma‐mediated effects on leukemia cells . However, it is also very important to monitor the vital state of stromal cells, as they are a source of protective and proleukemic signals.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, to mimic the bone marrow conditions, multiple studies of protective role of the bone marrow stroma utilize in vitro co‐culture of human stromal and leukemia cells. The simplistic model of 2D co‐culture, even if does not contain all types of bone marrow niche components, is sufficient for initial screening of anti‐ or proleukemic factors and is broadly used in in vitro studies . Even if the cross‐talk between leukemia and stromal cells leads to a rearrangement of cells’ functions, it is still crucial to control and monitor the fundamental cellular processes and basal vital parameters of stromal cells.…”

mentioning

confidence: 99%

Characteristics of live parameters of the HS‐5 human bone marrow stromal cell line cocultured with the leukemia cells in hypoxia, for the studies of leukemia–stroma cross‐talk

Podszywałow-Bartnicka

Kominek

Wolczyk

et al. 2018

Cytometry Pt A

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The unique bone marrow microenvironment is created by stromal cells and such physical conditions as hypoxia. Both hypoxia and interactions with stromal cells have a significant impact on the biology of leukemia cells, changing their sensitivity to antileukemic therapies. Thus, it is crucial to introduce biological systems, which enable the investigation of leukemia-stroma cross-talk and verification of novel therapies effectiveness under such bone marrow niche-mimicking conditions. Here, we have established an experimental setup based on the hypoxic co-culture of stromal cells with different cell lines derived from various leukemia patients. Flow cytometry enables simultaneous fluorescent tracking of viable cells and analysis of fundamental cellular processes, also to monitor the basal vital state of cells in the hypoxic co-culture. This is critically important, as the stromal cells deliver a big variability of signals to protect leukemia cells and provide drug resistance. Therefore, keeping stromal cells at the healthy state is crucial during experimental procedures. In the proposed studies, viability, apoptosis, proliferation, ROS production, and mitochondrial membrane potential were monitored in both cell types, which were separated on the basis of the fluorescence of a cell tracker. We have shown that the proposed hypoxic co-culture conditions do not affect basal live parameters of stromal cells, indicating the relevance of proposed model. Finally, we utilized this experimental setup to monitor the stroma-mediated protection of leukemia cells from the imatinib-induced cell death, which contributes to the leukemia progression and development of therapy resistance. Altogether, we recommend such flow cytometric strategy as an elementary screen of the vital state of stromal cells, which should be performed when using the co-culture hypoxic models. The proposed approach can also be broadly used for other studies of the leukemia-stroma cross-talk and of the part played by the leukemic microenvironment in drug screening studies.

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TGF-β1 and CXCL12 modulate proliferation and chemotherapy sensitivity of acute myeloid leukemia cells co-cultured with multipotent mesenchymal stromal cells

Abstract: These findings suggest a strong supporting affinity between MSCs and AML cells within the leukemic niche, where TGF-β1 and CXCL12 pathways play an important role.

Cited by 29 publications

References 30 publications

Hydroxyurea‐induced senescent peripheral blood mesenchymal stromal cells inhibit bystander cell proliferation of JAK2V617F‐positive human erythroleukemia cells

Hydroxyurea‐induced senescent peripheral blood mesenchymal stromal cells inhibit bystander cell proliferation of JAK2V617F‐positive human erythroleukemia cells

The Role of Mesenchymal Stem Cells in Atherosclerosis: Prospects for Therapy via the Modulation of Inflammatory Milieu

Characteristics of live parameters of the HS‐5 human bone marrow stromal cell line cocultured with the leukemia cells in hypoxia, for the studies of leukemia–stroma cross‐talk

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