Multiple sclerosis mesenchymal stromal cells exhibit a distinct gene expression profile and decreased immunosuppressive properties in relation to healthy control cells

Abstract Abstract 3810 Mesenchymal stromal cells (MSC) are a non-hematopoietic BM cell population considered to be not only the osteoblastic progenitors, but also a key component of the hematopoietic microenvironment. Raaijmakers et al (Nature, 2010) have recently shown that deletion of Dicer1 in MSC-derived osteoprogenitors as well as its target gene SBDS resulted in myelodysplasia (MDS) in a murine model. We have previously confirmed these results in human MSC from MDS patients (ASH 2010, # 397). In a previous paper (Leukemia, 2009) we showed that MSC from 5q- syndrome patients were different from MSC from other types of MDS and could be involved in their development. We have hypothesized that lenalidomide, the standard treatment of 5q- patients could act not only on hematopoietic progenitors but also on the BM microenvironment. For this purpose BM-MSC from healthy donors (HD) (n=7) and 5q- syndrome patients (n=5) were expanded in vitro and treated with 50 uM lenalidomide or its solvent (DMSO) as control. RNA was obtained from MSC and DICER1, DROSHA and SBDS relative gene expression was assessed by real-time PCR using TaqMan® assay as well as several microRNAs with known role in hematopoiesis and immune system regulation. In addition, MSC gene expression profile was studied. Labeled samples were hybridized to affymetrix of oligonucleotide HU 1.OST arrays in 5q- patients (n=4) and compared with MSCs from HD (n=3). For this purpose the ratio lenalidomide-treated sample and its paired DMSO control was calculated and markers with a fold change >1.5 were selected for hierarchical clustering analysis (HCA). MSCs from 5q-syndrome showed lower expression of DICER1 when compared with those from HD (.35 x10−3 vs.20 x10−3 p=0.03) but this expression was recovered when 5q-MSCs were treated with Lenalidomide (0.32 x10−3 p= 0.34). By contrast, no differences in DROSHA expression were observed. In addition, 5q-MSC showed SBDS lower expression than HD-MSC and in both groups the expression increased when they were treated with lenalidomide fig1). When microRNAs were analyzed, we observed a lower microRNA expression in lenalidomide-treated MSC from healthy donors when was compared to paired non-treated cells, especially for miRNA-155 (p=0.028), miRNA-222 (p=0.028),and miRNA-181a (p=0.075; Table 1). By contrast, lenalidomide-treated MSC from MDS showed a trend towards higher microRNA expression in comparison to paired non-treated MSC.Table 1.HD-MSC DMSO vs LENA5q-MSC DMSO vs LENAmiRNA 1460.50 vs 0.30p=0.2490.07 vs 0.10p=0.7miRNA 1500.004 vs 0.0065p=0.60.001 vs 0.006p=0.07miRNA 1550.90 vs 0.58p=0.0280.80 vs 0.96p=0.7miRNA 181a2.47 vs 1,83p=0.0751.66 vs 2.32p=0.07miRNA 22286.2 vs 68.0p=0.02843.2 vs 56.2p=0.07 When the gene expression profile was carried out based in 421 selected probes including 306 known genes, MSC-treated cells from 5q- were separated from HD MSC by HCA (Fig2). We can conclude that Lenalidomide not only acts on HPC from 5q- patients but also on microenvironment by modifying the expression of DICER-1 and SBDS as well as the expression of some microRNAs and genes. Disclosures: San Miguel: Celgene Corp.: Membership on an entity's Board of Directors or advisory committees. del Cañizo:Celgene Corp.: Spanishn Adviory committee.

Download Full-text

Comparative global gene expression profile of human limbal stromal cells, bone marrow mesenchymal stromal cells, adipose-derived mesenchymal stromal cells and foreskin fibroblasts

Stem Cell Biology and Research ◽

10.7243/2054-717x-1-1 ◽

2014 ◽

Vol 1 (1) ◽

pp. 1 ◽

Cited By ~ 1

Author(s):

Moon Nian Lim ◽

Noor Hamidah Hussin ◽

Ainoon Othman ◽

Thiageswari Umapathy ◽

Singh Gurbind ◽

...

Keyword(s):

Gene Expression ◽

Bone Marrow ◽

Gene Expression Profile ◽

Mesenchymal Stromal Cells ◽

Expression Profile ◽

Stromal Cells ◽

Global Gene Expression ◽

Global Gene Expression Profile

Download Full-text

Microarray Analysis of the Peripheral Monocytes From Waldenstrom's Macroglobulinemia Patients Reveals a Distinct Gene Expression Profile

Blood ◽

10.1182/blood.v116.21.2010.2010 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2010-2010

Author(s):

Jingrui Jiang ◽

Guang Yang ◽

Xia Liu ◽

Zachary Hunter ◽

Robert Manning ◽

...

Keyword(s):

Gene Expression ◽

Real Time ◽

Gene Expression Profile ◽

Expression Profile ◽

Real Time Pcr ◽

Peripheral Blood ◽

Waldenström’S Macroglobulinemia ◽

Distinct Gene ◽

Distinct Gene Expression Profile ◽

Waldenström's Macroglobulinemia

Abstract Abstract 2010 Background: Waldenstrom's macroglobulinemia (WM) is a B-cell malignancy characterized by the accumulation, predominantly in the bone marrow, of clonally related IgM-secreting lymphoplasmacytic cells. Macrophage derived inflammatory factors are elevated in WM suggesting a possible contribution by monocytes to the growth and survival of WM cells. Patients and Method: Monocytes (CD14+) from the peripheral blood of 8 untreated WM patients, and 6 healthy donors (HDs) were isolated by immunomagnetic bead sorting. Gene expression profiling was then performed using Human Genome U133 Plus 2.0 chips, and data obtained from microarray was analyzed by dChip software with fold change >=2 and p<=0.05 as cut off points. Validation was performed by real time PCR. Results: Using Panther classification, 284 transcripts were identified as significantly different in monocytes derived from WM patients versus HDs. The resulted transcripts are involved in many critical signaling pathways, such as Toll-like immune receptor pathway (i.e. TLR1, TLR4, TLR8, TICAM); inflammatory response (i.e. CD40, PTAFR, FPR2), integrin binding (i.e. RAC2, ILK), chemokinesis (i.e. CCR2, CX3CR1), apoptosis (i.e. TNFSF10), p53 signaling (i.e. GADD45A, 1433F) and G-protein coupled receptors (i.e. CX3CR1). Fifteen of 21 genes were validated by real-time PCR, and were over-expressed in peripheral blood monocytes from WM patients in comparison to healthy age matched donors: Conclusion: Peripheral monocytes from WM patients demonstrate a distinct gene expression profile characterized by up-regulation of genes affecting Toll-like innate immunity, inflammation, and apoptosis. These studies define a distinct microenvironmental signature, and provide a framework for the exploration of novel targets for prognosis and therapy in WM. Disclosures: No relevant conflicts of interest to declare.

Download Full-text