Boada Matilde, Echarte Lourdes, Guillermo Cecilia, Diaz Lilián, Touriño Cristina, Grille Sofía
Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
Hematol Transfus Cell Ther. 2021 Jan-Mar;43(1):35-42. doi: 10.1016/j.htct.2019.12.002. Epub 2020 Jan 27.
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematological diseases. In addition to defects in hematologic progenitor and stem cells, dysfunctions in the bone marrow microenvironment (BMM) participate in the MDS pathogenesis. Furthermore, the immune response is deregulated by the pro-inflammatory response prevailing in low-risk MDS, while immunosuppression predominates in high-risk MDS. Mesenchymal stromal cells (MSC), part of the BMM, are characterized by plastic adherent growth and multipotentiality. They exhibit immunomodulatory properties and sustain hematopoiesis. There is conflicting evidence regarding their status in MDS. The aim of this study was to characterize MDS-MSC and evaluate the effect of 5-Azacytidine.
The MSC from MDS patients and controls were cultured and characterized according to the International Society of Cell Therapy recommendations. Immunomodulatory properties were assessed by studying the MSD cytokine production, using the cytometric bead array. We evaluated the effect of 5-Azacytidine on the MSC cytokine production.
We included 35 MDS patients and 22 controls. The MSC from patients and controls were cultured and characterized. The MSC from patients showed morphological differences, but there were no differences in immunophenotype or multipotentiality. The interleukin 6 (IL-6) was the main MSC secreted cytokine. The MDS-MSC produced higher levels of IL-6, IL-17, interferon gamma, or interferon γ (INF-γ), and tumor necrosis factor alpha (TNF-α). The in vitro 5-Azacytidine treatment induced a significant decrease in the IL-6 production by MDS-MSC.
The MDS-MSC show an increased production of pro-inflammatory cytokines. The in vitro treatment with 5-Azacytidine lead to a significant reduction in the IL-6 production by the MDS-MSC, restoring the IL-6 levels to those found in controls. The MSC produced inflammatory cytokines involved in the MDS pathogenesis, representing a potential future therapeutic target. Moreover, 5-Azacytidine may have a stromal effect, modulating the immune response in MDS.
骨髓增生异常综合征（MDS）是一组异质性克隆性血液系统疾病。除造血祖细胞和干细胞存在缺陷外，骨髓微环境（BMM）功能障碍也参与了MDS的发病机制。此外，低危MDS中占主导的促炎反应使免疫反应失调，而高危MDS中免疫抑制占主导。间充质基质细胞（MSC）是BMM的一部分，其特点是贴壁生长且具有多能性。它们具有免疫调节特性并维持造血功能。关于它们在MDS中的状态存在相互矛盾的证据。本研究的目的是对MDS-MSC进行特征描述并评估5-氮杂胞苷的作用。
根据国际细胞治疗协会的建议，对MDS患者和对照的MSC进行培养和特征描述。通过流式细胞术微球阵列研究MSD细胞因子产生情况，评估免疫调节特性。我们评估了5-氮杂胞苷对MSC细胞因子产生的影响。
我们纳入了35例MDS患者和22例对照。对患者和对照的MSC进行培养和特征描述。患者的MSC表现出形态学差异，但免疫表型或多能性无差异。白细胞介素6（IL-6）是MSC分泌的主要细胞因子。MDS-MSC产生更高水平的IL-6、IL-17、干扰素γ（INF-γ）和肿瘤坏死因子α（TNF-α）。体外5-氮杂胞苷处理导致MDS-MSC产生的IL-6显著减少。
MDS-MSC促炎细胞因子的产生增加。体外5-氮杂胞苷处理导致MDS-MSC产生的IL-6显著降低，使IL-6水平恢复到对照中的水平。MSC产生的炎性细胞因子参与了MDS的发病机制，代表了未来潜在的治疗靶点。此外，5-氮杂胞苷可能具有基质效应，调节MDS中的免疫反应。
