Nathalie Meuleman

Institut Jules Bordet, Bruxelles, Brussels Capital, Belgium

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Publications (57)208.57 Total impact

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    ABSTRACT: MicroRNAs (or miRs) play a crucial role in chronic lymphocytic leukemia (CLL) physiopathology and prognosis. In addition, circulating microRNAs in body fluids have been proposed as new biomarkers. We investigated the expression of matched cellular and serum circulating microRNA-150 by real-time PCR (qPCR) from purified CD19+ cells or from CLL serums obtained at diagnosis in a cohort of 273/252 CLL patients with a median follow-up of 78 months (range, 7-380) and correlated it to other biological or clinical parameters. We showed that miR-150 was significantly overexpressed in CLL cells/serums compared to healthy subjects (P<0.0001). Among CLL patients, a low cellular miR-150 expression level was associated with tumor burden, disease aggressiveness and poor prognostic factors. In contrast, a high level of serum miR-150 was associated with tumor burden markers and some markers of poor prognosis. Similarly, cellular and serum miR-150 also predicted treatment-free (TFS) and overall survival (OS) in an opposite manner: patients with low cellular/serum miR-150 levels have median TFS of 40/111 months compared with high level patients who have median TFS of 122/60 months (P<0.0001/P=0.0066). Similar results have been observed for OS. We also found that cellular and serum miR-150 levels vary in an opposite manner during disease progression and that cellular miR-150 could be regulated by its release into the extracellular space. Cellular and serum levels of miR-150 are associated with opposite clinical prognoses and could be used to molecularly monitor disease evolution as a new prognostic factor in CLL.
    Molecular medicine (Cambridge, Mass.). 01/2015;
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    ABSTRACT: In multiple myeloma (MM), bone marrow mesenchymal stromal cells (BM-MSCs) play an important role in pathogenesis and disease progression by supporting myeloma cell growth and immune escape. Previous studies have suggested that direct and indirect interactions between malignant cells and BM-MSCs result in constitutive abnormal immunomodulatory capacities in MM BM-MSCs. The aim of this study was to investigate the mechanisms that underlie these MM BM-MSCs abnormalities. We demonstrated that MM BM-MSCs exhibit abnormal expression of CD40/40L, VCAM1, ICAM-1, LFA-3, HO-1, HLA-DR and HLA-ABC. Furthermore, an overproduction of IL-6 (1,806 ± 152.5 vs 719.6 ± 18.22 ng/mL; p = 0.035) and a reduced secretion of IL-10 (136 ± 15.02 vs 346.4 ± 35.32 ng/mL; p = 0.015) were quantified in culture medium when MM BM-MSCs were co-cultured with T lymphocytes compared to co-cultures with healthy donor (HD) BM-MSCs. An increased Th17/Treg ratio was observed when T cells were co-cultured with MM BM-MSCs compared to co-cultures with HD BM-MSCs (0.955 vs 0.055). Together, these observations demonstrated that altered immunomodulation capacities of MM BM-MSCs were linked to variations in their immunogenicity and secretion profile. These alterations lead not only to a reduced inhibition of T cell proliferation but also to a shift in the Th17/Treg balance. We identified factors that are potentially responsible for these alterations, such as IL-6, VCAM-1 and CD40, which could also be associated with MM pathogenesis and progression.
    Cancer Immunology and Immunotherapy 10/2014; 64(2). · 3.94 Impact Factor
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    ABSTRACT: Histone deacetylases (HDAC) play a crucial role in transcriptional regulation and are often deregulated in many cancers. However, global HDAC enzymatic activity has never been investigated in Chronic Lymphocytic Leukemia (CLL). We measured HDAC activity in protein extracts from CD19+ B-cells purified from 114 CLL patients with a median follow-up of 91 months (range: 11-376). HDAC activity was equivalent in CLL and normal B-cells but higher in patients who died during the study than in living patients (152.1 vs. 65.04 pmol; P = 0.0060). Furthermore, HDAC activity correlated with treatment-free survival (TFS; P = 0.0156) and overall survival (OS; P < 0.0001): patients with low HDAC activity (n = 75) had a median TFS and OS of 101 and >376 months, respectively, whereas patients with high HDAC activity (n = 39) had a median TFS and OS of 47 and 137 months, respectively. Multivariate analyses indicated that HDAC activity is an independent predictor of OS (hazard ratio = 7.68; P = 0.0017). Finally, HDAC activity increased after B-cell receptor stimulation using IgM, suggesting a role for microenvironment stimuli (n = 10; P = 0.0371). In conclusion, high HDAC activity in CLL B-cells is associated with shorter TFS and OS and is an independent marker of OS, refining the use of other prognostic factors. This work provides a biological base for the use of HDAC inhibitors in CLL treatment.
    Epigenetics: official journal of the DNA Methylation Society 10/2014; 9(10):1374-81. · 5.11 Impact Factor
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    ABSTRACT: Stem cell therapy is a potential method for the treatment of numerous diseases. The most frequent cellular source is bone marrow-derived mesenchymal stromal cells (BM-MSC). Human adipose-derived stromal cells (ADSC) share similar properties with BM-MSC as they support hematopoiesis, modulate ongoing immune responses and differentiate into cells of mesodermal origin. On the other hand, ADSC have higher frequency in situ, higher availability and very few ethical issues compared to BM-MSC giving them an advantage over BM-MSC for clinical use. Most of the methods used to isolate ADSC contain a collagenase digestion step, but the type of collagenase and time of sample digestion vary among studies and these differences could have an impact on the cell properties and thus in result comparison. To overcome this obstacle, we propose a new method to isolate ADSC from lipoaspirate without collagenase digestion step. We compared ADSC obtained with our method versus classical protocol using collagenase digestion. Cells obtained with our method are equivalent but has a better long term hematopoietic support than those obtained with classical method. Moreover, our method has an advantage over the classical one as it is easier, safer, faster, less expensive and more consistent with good manufacturing practices (GMP) to obtain large number of ADSC ex vivo.
    Stem cells and development 05/2014; · 4.15 Impact Factor
  • Journal of Geriatric Oncology 10/2013; 4:S56. · 1.15 Impact Factor
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    ABSTRACT: Monoclonal gammopathy of undetermined significance (MGUS) is a frequent condition affecting at least 3% of the general population over 50 years. Usually, the diagnosis of MGUS is made accidentally during a biological assessment for other conditions. Although MGUS is most frequently a benign and asymptomatic disorder, it has well been described that MGUS could be a premalignant status and that the risk of transformation into myeloma or other lymphoproliferative disorders is estimated at 1% per year. MGUS can also be associated with other diseases than malignant disorders such as Infections, autoimmune diseases. In some case it could reflect rare but severe disorders that will be crucial not to miss the diagnosis.
    Revue medicale de Bruxelles 09/2013; 34(4):335-8.
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    ABSTRACT: Autologous mesenchymal stromal cell (MSC)-based therapies offer one of the most promising and safe methods for regeneration or reconstruction of tissues and organs. Routinely procedures to obtain adequate amount of autologous stem cells need their expansion through culture, with risks of contamination and cell differentiation, leading to loss of cell ability for therapies. We suggest the use of human bone marrow as a physiological bioreactor to produce autologous MSC by injection of autologous platelet-rich plasma (PRP) activated by recombinant human soluble tissue factor (rhsTF) in iliac crest. A trial on thirteen healthy volunteers showed the feasibility and harmlessness of the procedure. The phenotype and cellularity of bone marrow cells were not modified, on day 3 after injection. Endothelial progenitor cells (EPC) were mobilized to bloodstream, without stimulation of hematopoietic stem cells (HSC). MSC level in bone marrow increased with a specific commitment to preosteoblastic cell population both in vivo and in vitro. This self-stimulation system of bone marrow seems thus to be a promising feasible process three days prior to clinical cell therapy applications.
    Tissue Engineering Part A 08/2013; · 4.64 Impact Factor
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    ABSTRACT: The prevalence of monoclonal gammopathy of undetermined significance (MGUS) is generally estimated at 3.4% in the general population over 50 years, and its incidence increases with age. MGUS represents a preneoplastic entity that can transform into multiple myeloma or other lymphoproliferative disorders. The risk of malignant transformation is estimated at 1% per year and persists over time. Predictors of malignant transformation have been identified such as the heavy chain isotype, The level of monoclonal proteins, increasing levels of the monoclonal component during the first years off follow-up, the percentage of bone marrow plasmocytosis, the dosage of serum free light chains, the presence of immunophenotypically abnormal plasma cells, aneuploidy, and the presence of circulating plasma cells. Prognostic scores that combine certain of these factors have been proposed and allow the identification of high-risk patients. Their use could assist in tailoring the care for each patient, based on his/her risk profile.
    Annals of Medicine 06/2013; · 4.73 Impact Factor
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    ABSTRACT: In multiple myeloma, bone marrow mesenchymal stromal cells support myeloma cell growth. Previous studies have suggested that direct and indirect interactions between malignant cells and bone marrow mesenchymal stromal cells result in constitutive abnormalities in the bone marrow mesenchymal stromal cells. The aims of this study were to investigate the constitutive abnormalities in myeloma bone marrow mesenchymal stromal cells and to evaluate the impact of new treatments. We demonstrated that myeloma bone marrow mesenchymal stromal cells have an increased expression of senescence-associated β-galactosidase, increased cell size, reduced proliferation capacity and characteristic expression of senescence-associated secretory profile members. We also observed a reduction in osteoblastogenic capacity and immunomodulatory activity and an increase in hematopoietic support capacity. Finally, we determined that current treatments were able to partially reduce some abnormalities in secreted factors, proliferation and osteoblastogenesis. We showed that myeloma bone marrow mesenchymal stromal cells have an early senescent profile with profound alterations in their characteristics. This senescent state most likely participates in disease progression and relapse by altering the tumor microenvironment.
    PLoS ONE 03/2013; 8(3):e59756. · 3.53 Impact Factor
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    Journal of Cancer Science and Therapy 11/2012; 4(12):394-400.
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    ABSTRACT: Histone deacetylases (HDACs) play a crucial role in chromatin structure and, consequently, gene expression. Their deregulation has been reported in various cancers. We performed a complete and comprehensive study of the expression of 18 HDACs (including Sirtuin; SIRT) by real-time PCR in a cohort of 200 chronic lymphocytic leukemia (CLL) patients with a median follow-up of 77 mo, and compared it with the results obtained from normal B cells. We also compared HDAC expression at diagnosis and after relapse. We observed significant deregulation (mostly upregulation) of HDACs in CLL. In terms of clinical significance, only HDAC6 was significantly correlated with treatment-free survival (TFS), whereas HDAC3 and SIRT2, 3 and 6 were correlated with overall survival (OS). A multivariate Cox regression stepwise analysis indicated that HDAC6, 7 and 10 and SIRT3 were TFS independent predictors. Interestingly, poor prognosis was associated with an overexpression of HDAC7 and 10 but an under expression of HDAC6 and SIRT3. Therefore, these factors were combined in a TFS score: patients with a score of 0-1-2, 3 and 4 had a median TFS of 107, 57 and 26 mo, respectively. For OS, SIRT5 and 6 allowed stratification into 3 groups, with a median OS of > 360, 237 and 94 mo. However, we could not find statistical differences in HDAC expression after relapse. These results, validated by a 5-fold cross-validation, highlight the complex impact of HDAC expression in CLL clinical course.
    Epigenetics: official journal of the DNA Methylation Society 10/2012; 7(12). · 5.11 Impact Factor
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    ABSTRACT: Intraarterial administration of 90Y microspheres to the spleen in patients with malignant lymphoma was mentioned once in the literature in 1973. This case study illustrates the potential indication of selective internal radiotherapy in a heavily pretreated patient with highly refractory disease with a marginal zone lymphoma in leukemic phase and symptomatic splenomegaly. We describe the clinical course of disease; the biological and clinical response to the treatment after radioembolization; and simulation and dosimetry by multimodal imaging via single-photon emission computed tomography and computed tomography. The advantages of radioembolization for the management of lymphomatous splenomegaly are discussed.
    CardioVascular and Interventional Radiology 09/2012; · 2.09 Impact Factor
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    ABSTRACT: Mesenchymal stromal cells (MSCs) possess a specific immunological profile that makes them potentially useful for immune-based therapies. Adipose tissue (AT) and Wharton's jelly (WJ) are considered to be valuable alternatives to bone marrow (BM) as sources of MSCs. These MSCs exhibit strong immunomodulatory properties that affect lymphocyte responses. The CD200/CD200R axis has been reported to be important in regulating the immune responses. Engagement of CD200R by CD200 initiates an inhibitory pathway that displays immunosuppressive effects. Because the CD200/CD200R axis is involved in immunoregulation, we investigated the expression and role of this ligand/receptor pair in MSCs and T-lymphocytes during co-culture. CD200 is differently expressed and modulated on MSCs depending on the tissue of origin and the culture conditions. Among the different MSC sources, WJ-MSCs express CD200 in the greatest proportion. This high constitutive CD200 expression may represent a distinctive marker for WJ-MSCs. A pro-inflammatory environment and IFN-γ in particular induce an increase in CD200 expression by BM-MSCs. In T-lymphocytes, CD200R and CD200 are differently distributed between the CD4(+) and CD8(+) T-cell subsets. During co-culture, blocking CD200-CD200R interactions does not prevent MSC-mediated inhibition of lymphocyte proliferation. However, depending on their origin, MSCs are able to modulate the expression of both CD200 and CD200R on some T-cells. Further study is required to understand the function of CD200 expression by nonmyeloid cells such MSCs and the significance of CD200 and C200R expression by T-cells. The findings presented here support bidirectional communication between MSCs and T-lymphocytes. Understanding the role of this ligand-receptor pair during co-culture will improve and increase the clinical use of MSCs.
    Immunology letters 05/2012; 146(1-2):50-6. · 2.91 Impact Factor
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    ABSTRACT: Mesenchymal stromal cells (MSCs) can be isolated not only from bone marrow (BM) but also from other tissues, including adipose tissue (AT) and umbilical cord Wharton's Jelly (WJ). Thanks to their ability to differentiate into various cell types, MSC are considered attractive candidates for cell-based regenerative therapy. In degenerative clinical settings, inflammation or infection is often involved. In the present work, we hypothesized that an inflammatory environment and/or Toll-like receptor (TLR) ligation could affect the MSC differentiation potential. MSC were isolated from BM, AT, and WJ. Inflammation was mimicked by a cytokine cocktail, and TLR activation was induced through TLR3 and TLR4 ligation. Osteogenesis was chosen as a model for differentiation. Osteogenic parameters were evaluated by measuring Ca2+ deposits and alkaline phosphatase (ALP) activity at day 7, 14, and 21 of the culture in an osteogenic medium. Our results show that WJ-MSC exhibit a much lower osteogenic potential than the other two MSC types. However, inflammation was able to strongly increase the osteogenic differentiation of WJ-MSC as calcification, and ALP activity appeared as early as day 7. However, this latter enzymatic activity remained much lower than that disclosed by BM-MSC. TLR3 or TLR4 triggering increased the osteogenesis in AT- and, to lesser extent, in BM-MSC. In conclusion, WJ-MSC constitutively disclose a lower osteogenic potential as compared with BM and AT-MSC, which is not affected by TLR triggering but is strongly increased by inflammation, then reaching the level of BM-MSC. These observations suggest that WJ-MSC could constitute an alternative of BM-MSC for bone regenerative applications, as WJ is an easy access source of large amounts of MSC that can effectively differentiate into osteoblasts in an inflammatory setting.
    Tissue Engineering Part A 03/2012; 18(13-14):1410-8. · 4.64 Impact Factor
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    ABSTRACT: Interactions with the microenvironment, such as bone marrow mesenchymal stromal cells and nurse-like cells, protect chronic lymphocytic leukemia cells from spontaneous and drug-induced apoptosis. This protection is partially mediated by the chemokine SDF-1α (CXCL12) and its receptor CXCR4 (CD184) present on the chronic lymphocytic leukemia cell surface. Here, we investigated the ability of AMD3100, a CXCR4 antagonist, to sensitize chronic lymphocytic leukemia cells to chemotherapy in a chronic lymphocytic leukemia/mesenchymal stromal cell based or nurse-like cell based microenvironment co-culture model. AMD3100 decreased CXCR4 expression signal (n=15, P=0.0078) and inhibited actin polymerization/migration in response to SDF-1α (n=8, P<0.01) and pseudoemperipolesis (n=10, P=0.0010), suggesting that AMD3100 interferes with chronic lymphocytic leukemia cell trafficking. AMD3100 did not have a direct effect on apoptosis when chronic lymphocytic leukemia cells were cultured alone (n=10, P=0.8812). However, when they were cultured with SDF-1α, mesenchymal stromal cells or nurse-like cells (protecting them from apoptosis, P<0.001), chronic lymphocytic leukemia cell pre-treatment with AMD3100 significantly inhibited these protective effects (n=8, P<0.01) and decreased the expression of the anti-apoptotic proteins MCL-1 and FLIP. Furthermore, combining AMD3100 with various drugs (fludarabine, cladribine, valproïc acid, bortezomib, flavopiridol, methylprednisolone) in our mesenchymal stromal cell co-culture model enhanced drug-induced apoptosis (n=8, P<0.05) indicating that AMD3100 could mobilize chronic lymphocytic leukemia cells away from their protective microenvironment, making them more accessible to conventional therapies. Taken together, these data demonstrate that interfering with the SDF-1α/CXCR4 axis by using AMD3100 inhibited chronic lymphocytic leukemia cell trafficking and microenvironment-mediated protective effects. Combining AMD3100 with other drugs may, therefore, represent a promising therapeutic approach to kill chronic lymphocytic leukemia cells.
    Haematologica 11/2011; 97(4):608-15. · 5.94 Impact Factor
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    ABSTRACT: Mesenchymal stromal cells (MSC) can be expanded from different sources. We compared the influence of inflammation and TLR ligation on the phenotype and function of MSC derived from bone marrow (BM), adipose tissue (AT), and Wharton's jelly (WJ). WJ-MSC were featured by a lack of TLR4 expression. While inflammation upregulated TLR3 in all three MSC types, TLR4 upregulation was observed only on BM-MSC. TLR ligation increased the production of inflammatory cytokines in BM- and AT-MSC but not in WJ-MSC and augmented anti-inflammatory cytokines in AT-MSC. Although inflammation increased in all MSC types the secretion of inflammatory cytokines, additional TLR triggering did not have further effect on WJ-MSC. The immunosuppressive potential of WJ-MSC on MLR was affected neither by inflammation nor by TLR triggering. This resistance was related to an overproduction of HGF. These data indicate that MSC source could be of importance while designing immunomodulating cell therapy in transplantation.
    Cellular Immunology 05/2011; 270(2):207-16. · 1.87 Impact Factor
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    ABSTRACT: Mesenchymal stromal cells (MSCs) possess immunomodulatory functions and have been proposed as a tool for managing or preventing graft-versus-host disease. Recently, adipose tissue (AT) and Wharton's jelly (WJ) have been reported as potential alternative MSC sources to bone marrow (BM). In this study, we investigated the capacity of MSCs derived from AT and WJ to modulate lymphocyte proliferation as well as their impact on regulatory T-cells. We also evaluated MSC expression of leukemia inhibitory factor and the role of this molecule in the mechanism of MSC-mediated inhibition. We demonstrated that WJ- and AT-MSCs induced a dose-dependent inhibition of T-cell proliferation regardless of the stimuli used to activate T-cells. WJ- and AT-MSCs were more potent than BM-MSCs in suppressing lymphocyte responses, and they mediated this effect by secreting high levels of leukemia inhibitory factor. We also observed that WJ- and AT-MSCs maintained and promoted the expansion of regulatory T-cells independently of the MSC/T-cell ratio. Because human WJ and AT contain MSCs with potent immunomodulatory capacities, they could represent an alternative to BM. Using WJ- and AT-MSCs in clinical therapies, such as the prevention and/or reduction of graft-versus-host disease and in the treatment of autoimmune diseases, is particularly promising. Further characterization of MSC physiological functions will increase the safety and efficacy of their use in clinical settings.
    Tissue Engineering Part A 11/2010; 16(11):3537-46. · 4.64 Impact Factor
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    ABSTRACT: As mesenchymal stromal cells (MSCs) have been proposed as a tool for management or prevention of graft-vs-host disease, we investigated their immunoregulatory properties, their expression of adhesion molecules and galectin-1, and the impact of environment context on these functions. The effects of MSCs on T-cell proliferation were analyzed using carboxyfluorescein diacetate N-succinimidyl ester labeling. We evaluated the expression of adhesion molecules and galectin-1 by MSCs and the impact of an inflammatory or infectious environment on these expressions. Using neutralizing antibodies against adhesion molecules and a galectin-1 inhibitor, we assessed the role of these molecules in MSC functions. MSCs inhibition of T-cell proliferation depended on MSC concentrations, cell contact, and culture environment. Expression of adhesion molecules and secretion of galectin-1 by MSCs are tightly regulated. Coculture with activated T cells upregulated expression of CD54 (intercellular adhesion molecule 1) and CD58 (lymphocyte function-associated antigen 3) and secretion of galectin-1 by MSCs. Interestingly, in an inflammatory or infectious environment, expression of adhesion molecules and galectin-1 by MSCs was differentially modulated. Furthermore, blocking galectin-1 activity prevented the suppressive potential of MSCs. Neutralization of adhesion molecule activity had no effect on MSC inhibition. Galectin-1 plays an important role in MSC immunoregulatory functions, which are depending on cell environment. The present study provides new insights concerning MSC physiology and will increase the safety and efficiency of MSCs in clinical settings.
    Experimental hematology 10/2010; 38(10):922-32. · 3.11 Impact Factor
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    ABSTRACT: The co-infusion of mesenchymal stromal cells (MSCs) with hematopoietic stem cells could improve the hematopoietic engraftment after cord blood transplant. Adult bone marrow is the major source of MSCs for cell therapy. However, bone marrow aspiration involves an invasive procedure and, in the case of a cord blood transplant, requires the use of a third party. The umbilical cord matrix, called Wharton's jelly (WJ), was previously shown to be a valuable source of MSCs. However, the process of cell separation is not standardized and needs to be optimized. In this study, we focused on the efficiency of the isolation procedure and expansion of cells from WJ MSCs isolated from human full-term umbilical cords. MSCs were isolated from the WJ without enzyme digestion or dissection. The procedure was based only on the plastic adhesion capacities of MSCs. Briefly, umbilical cord segments of 5-10 cm were cut longitudinally and plated with the WJ onto a plastic surface for 5 days in an appropriate culture medium. After removing the cord segment, the culture was pursued until subconfluency. The number of cells and their phenotypes, clonogenic capacities, differentiation capacities, immunomodulation, and hematopoietic supportive functions were evaluated. Using this method, we were able to isolate MSCs from all human umbilical cords analyzed (n = 50). We obtained a mean of 1.4 × 10(8) cells at the second passage and >7 × 10(9) cells at the third. The expanded cells expressed characteristic markers and presented typical functional properties of MSCs such as differentiation capacities, immunologic properties, and hematopoietic supportive functions. In conclusion, we have established a simple, rapid, and reproducible protocol to isolate abundant MSCs from short segments of umbilical cords.
    Stem cells and development 10/2010; 20(3):547-57. · 4.15 Impact Factor

Publication Stats

1k Citations
208.57 Total Impact Points


  • 2005–2014
    • Institut Jules Bordet
      Bruxelles, Brussels Capital, Belgium
  • 2013
    • University of Innsbruck
      Innsbruck, Tyrol, Austria
  • 2003–2011
    • Université Libre de Bruxelles
      • • Laboratory of Experimental Hematology
      • • Bordet Institute
      • • Department of Hematology
      Brussels, BRU, Belgium