The Different Immunoregulatory Functions on Dendritic Cells between Mesenchymal Stem Cells Derived from Bone Marrow of Patients with Low-Risk or High-Risk Myelodysplastic Syndromes

Wang, Zhenling; Tang, Xiaoqiong; Xu, Wei; Cao, Zhen-Dong; Sun, Li; Li, Weiming; Li, Qiubai; Zou, Ping; Zhao, Zhigang

doi:10.1371/journal.pone.0057470

Cited by 35 publications

(30 citation statements)

References 30 publications

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“…Remarkably, this effect was only observed in cells from low-risk MDS, whereas immunosuppressive functions of high-risk MDS-derived MSCs were similar to those of controls. 86 These results indicate that, despite not belonging to the malignant clone, the functionality of MSCs is altered in MDS and may favor the expansion of cytotoxic T cells in the early stages of the disease.…”

Section: Inflammation and Innate Immunity In Other Cell Typesmentioning

confidence: 78%

Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes

et al. 2015

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Myelodysplastic syndromes (MDSs) are a group of heterogeneous clonal hematologic malignancies that are characterized by defective bone marrow (BM) hematopoiesis and by the occurrence of intramedullary apoptosis. During the past decade, the identification of key genetic and epigenetic alterations in patients has improved our understanding of the pathophysiology of this disease. However, the specific molecular mechanisms leading to the pathogenesis of MDS have largely remained obscure. Recently, essential evidence supporting the direct role of innate immune abnormalities in MDS has been obtained, including the identification of multiple key regulators that are overexpressed or constitutively activated in BM hematopoietic stem and progenitor cells. Mounting experimental results indicate that the dysregulation of these molecules leads to abnormal hematopoiesis, unbalanced cell death and proliferation in patients' BM, and has an important role in the pathogenesis of MDS. Furthermore, there is compelling evidence that the deregulation of innate immune and inflammatory signaling also affects other cells from the immune system and the BM microenvironment, which establish aberrant associations with hematopoietic precursors and contribute to the MDS phenotype. Therefore, the deregulation of innate immune and inflammatory signaling should be considered as one of the driving forces in the pathogenesis of MDS. In this article, we review and update the advances in this field, summarizing the results from the most recent studies and discussing their clinical implications.

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Section: Inflammation and Innate Immunity In Other Cell Typesmentioning

confidence: 78%

Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes

et al. 2015

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“…In fact, the immunoregulatory role of MSC has been reported to be different between LR-MDS and HR-MDS. 9,33 It remains to be investigated whether different primary defects are present in MSC from LR and HR patients with MDS, which may contribute to the different biological characteristics of LR-MDS and HR-MDS.…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of Dicer1 promotes cellular senescence and decreases the differentiation and stem cell-supporting capacities of mesenchymal stromal cells in patients with myelodysplastic syndrome

Zhao¹,

Wu²,

Fei³

et al. 2014

Haematologica

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ABSTRACTdence suggests that microRNA (miRNA, miR) are functionally involved in MSC senescence. [18][19][20] The ablation of Dicer1 (an RNAse III endonuclease essential for miRNA biogenesis) and the loss of mature miRNA in embryonic fibroblasts and endothelial cells inhibited cell proliferation and induced a premature senescence phenotype. 21,22 Although recent striking findings indicate that Dicer1 deletion can induce an MDS phenotype in mice 23 and that Dicer1 expression is reduced in MSC from MDS patients, 24 the precise mechanism by which the Dicer1 gene contributes to the pathogenesis of MDS remains elusive. We inferred that disordered expression of Dicer1 could contribute to abnormal MSC senescence and impaired stromal support in MDS.The aims of this study were, therefore, to evaluate the senescent features of BM-MSC from patients with MDS and to explore the role of Dicer1 in the senescence of MSC and the disturbed stromal function observed in patients with MDS. Methods Patients and control samplesA total of 77 patients with MDS were included in this study. Their characteristics are detailed in Online Supplementary Table S1. Patients were diagnosed with MDS according to the minimum diagnostic criteria established by the Conference on MDS. 25Patients were classified for the study as "lower-risk" (LR) [International Prognostic Scoring System (IPSS) low/int-1] and as "higher-risk" (HR) (IPSS-int-2/high).26 Twenty-two healthy volunteers were used as controls (median age 62 years; age range, 43-78 years) and were matched for gender and age. All study participants signed an informed consent form. The research was approved by the ethics committee of the Sixth Hospital affiliated with Shanghai Jiao Tong University, and all patient-relevant research strictly abided by the Declaration of Helsinki. Mesenchymal stromal cell characterizationBM-MSC were isolated and cultured; their immunophenotype, clonogenic and proliferative potential, and differentiation were studied and SA-β-Gal assay were performed. Detailed information about the experiments is provided in the Online Supplementary Material. RNA isolation and real-time polymerase chain reaction analysisTotal RNA was isolated using TRIzol (Invitrogen, Paisley, Scotland) according to the manufacturer's instructions. For mRNA detection, the RNA was reverse transcribed using the RevertAid First Strand cDNA Synthesis Kit (Fermentas, Burlington, Canada) according to the manufacturer's protocol, and real-time polymerase chain reaction (RT-PCR) was performed using RealMasterMix (Takara, Dalian, China). The process used was described in detail in our previous study. 27 The primers are listed in Online Supplementary Table S2. RT-PCR for miRNA was performed using the PrimeScript ™ miRNA qPCR Starter Kit Ver. 2.0 (Takara, Dalian, China). RNU6B was used as the housekeeping gene. Fold change was calculated using the DDCT method of relative quantification. Isolation of CD34 + cells and CD271 + cellsMononuclear cells were obtained from BM aspirates by density gradient separation and...

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“…Indeed, Wang et al described that mesenchymal stem cells derived from highrisk MDS patients impaired functions of dendritic cells, including IL12 secretion. 67 On the other hand, levels of IFNg, Th 1 cytokine, which is a crucial mediator of the IL12-primed immune responses, were not significantly changed among the MDS patients, as compared to healthy individuals. So the clinical significance of the IL12 downregulation is unclear, especially considering the effects of another IL12-family member, IL27 that also plays a role in the Th 1 -response activation.…”

mentioning

confidence: 88%

Dynamic alterations of bone marrow cytokine landscape of myelodysplastic syndromes patients treated with 5-azacytidine

et al. 2016

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Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal stem cell disorders characterized by ineffective hematopoiesis frequently progressing into acute myeloid leukemia (AML), with emerging evidence implicating aberrant bone marrow (BM) microenvironment and inflammationrelated changes. 5-azacytidine (5-AC) represents standard MDS treatment. Besides inhibiting DNA/RNA methylation, 5-AC has been shown to induce DNA damage and apoptosis in vitro. To provide insights into in vivo effects, we assessed the proinflammatory cytokines alterations during MDS progression, cytokine changes after 5-AC, and contribution of inflammatory comorbidities to the cytokine changes in MDS patients. We found that IL8, IP10/CXCL10, MCP1/CCL2 and IL27 were significantly elevated and IL12p70 decreased in BM of MDS low-risk, high-risk and AML patients compared to healthy donors. Repeated sampling of the high-risk MDS patients undergoing 5-AC therapy revealed that the levels of IL8, IL27 and MCP1 in BM plasma were progressively increasing in agreement with in vitro experiments using several cancer cell lines. Moreover, the presence of inflammatory diseases correlated with higher levels of IL8 and MCP1 in low-risk but not in high-risk MDS. Overall, all forms of MDS feature a deregulated proinflammatory cytokine landscape in the BM and such alterations are further augmented by therapy of MDS patients with 5-AC.

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The Different Immunoregulatory Functions on Dendritic Cells between Mesenchymal Stem Cells Derived from Bone Marrow of Patients with Low-Risk or High-Risk Myelodysplastic Syndromes

Cited by 35 publications

References 30 publications

Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes

Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes

Down-regulation of Dicer1 promotes cellular senescence and decreases the differentiation and stem cell-supporting capacities of mesenchymal stromal cells in patients with myelodysplastic syndrome

Dynamic alterations of bone marrow cytokine landscape of myelodysplastic syndromes patients treated with 5-azacytidine

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