scholarly journals Multiple Myeloma Cells Alter Adipogenesis, Increase Senescence-Related and Inflammatory Gene Transcript Expression, and Alter Metabolism in Preadipocytes

2021 ◽  
Vol 10 ◽  
Author(s):  
Heather Fairfield ◽  
Samantha Costa ◽  
Carolyne Falank ◽  
Mariah Farrell ◽  
Connor S. Murphy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Lipid Accumulation ◽  
Expression Profiles ◽  
Adipogenic Differentiation ◽  
Gene Expression Profiles ◽  
Mouse Bone Marrow ◽  
Gene Transcript ◽  
Bone Marrow Mscs

Within the bone marrow microenvironment, mesenchymal stromal cells (MSCs) are an essential precursor to bone marrow adipocytes and osteoblasts. The balance between this progenitor pool and mature cells (adipocytes and osteoblasts) is often skewed by disease and aging. In multiple myeloma (MM), a cancer of the plasma cell that predominantly grows within the bone marrow, as well as other cancers, MSCs, preadipocytes, and adipocytes have been shown to directly support tumor cell survival and proliferation. Increasing evidence supports the idea that MM-associated MSCs are distinct from healthy MSCs, and their gene expression profiles may be predictive of myeloma patient outcomes. Here we directly investigate how MM cells affect the differentiation capacity and gene expression profiles of preadipocytes and bone marrow MSCs. Our studies reveal that MM.1S cells cause a marked decrease in lipid accumulation in differentiating 3T3-L1 cells. Also, MM.1S cells or MM.1S-conditioned media altered gene expression profiles of both 3T3-L1 and mouse bone marrow MSCs. 3T3-L1 cells exposed to MM.1S cells before adipogenic differentiation displayed gene expression changes leading to significantly altered pathways involved in steroid biosynthesis, the cell cycle, and metabolism (oxidative phosphorylation and glycolysis) after adipogenesis. MM.1S cells induced a marked increase in 3T3-L1 expression of MM-supportive genes including Il-6 and Cxcl12 (SDF1), which was confirmed in mouse MSCs by qRT-PCR, suggesting a forward-feedback mechanism. In vitro experiments revealed that indirect MM exposure prior to differentiation drives a senescent-like phenotype in differentiating MSCs, and this trend was confirmed in MM-associated MSCs compared to MSCs from normal donors. In direct co-culture, human mesenchymal stem cells (hMSCs) exposed to MM.1S, RPMI-8226, and OPM-2 prior to and during differentiation, exhibited different levels of lipid accumulation as well as secreted cytokines. Combined, our results suggest that MM cells can inhibit adipogenic differentiation while stimulating expression of the senescence associated secretory phenotype (SASP) and other pro-myeloma molecules. This study provides insight into a novel way in which MM cells manipulate their microenvironment by altering the expression of supportive cytokines and skewing the cellular diversity of the marrow.

Genome-Wide Profiling of Endothelial Progenitor Cells in Multiple Myeloma: Overlaps with Myeloma Tumor Cells and Common Cancer Gene-Pathways.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 394-394
Author(s):  
Marc J. Braunstein ◽  
Daniel R. Carrasco ◽  
Fabien Campagne ◽  
Piali Mukherjee ◽  
Kumar Sukhdeo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Progenitor Cells ◽  
Tumor Cells ◽  
Expression Profiling ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cancer Biomarkers ◽  
Genome Wide

Abstract Background: In multiple myeloma (MM), bone-marrow-derived endothelial progenitor cells (EPCs) contribute to tumor neoangiogenesis, and their levels covary with tumor mass and prognosis. Recent X-chromosome inactivation studies showed that EPCs are clonally restricted in MM. In addition, high-resolution array comparative genomic hybridization (aCGH) found that the genomes of EPCs and MM cells display similar chromosomal gains and losses in the same patient. In this study, we performed an integrative analysis of EPCs and tumor cells by genome-wide expression profiling, and applied a bioinformatics approach that leverages gene expression data from cancer datasets to mine MM gene pathways common to multiple tumor tissues and likely involved in MM pathogenesis. Methods: Confluent EPCs (>98% vWF/CD133/KDR+ and CD38−) were outgrown from 22 untreated MM patients’ bone marrow aspirates by adherence to laminin. The fractions enriched for tumor cells were >50% CD38+. For gene expression profiling, total RNA from EPCs, MM cells, and control HUVECs were hybridized to cDNA microarrays, and comparisons were made by analysis of variance. Results: Two sets of EPC gene profiles were of particular interest. The first contained genes that differ significantly between EPCs and HUVEC, but not between EPCs and tumor (Profile 1). We hypothesize that this profile is a consequence of the clonal identity previously reported between EPCs and tumor, and that a subset of these genes is largely responsible for MM progression. The second set of important EPC genes are differentially regulated compared both to HUVECs and to tumor cells (Profile 2). These genes may represent the profile of EPCs that are clonally diverse from tumor cells but nevertheless display common gene expression patterns with other cancers. Profile 2 genes may also represent genes that confer a predisposition to clonal transformation of EPCs. When genes in Profile 1 and Profile 2 were overlapped with published lists of cancer biomarkers, significant similarities (P<.05) were apparent. The largest overlaps were observed with the HM200 gene list, a list composed of 200 genes most consistently differentially expressed in human/mouse cancers (Campagne and Skrabanek, BMC Bioinformatics 2006). More than 80% of genes in either EPC profile have not been previously characterized in MM, but have been identified as cancer biomarkers in other cancer studies. These genes will be presented and discussed in the context of MM. Current studies are aimed at integrating Profile 1 and Profile 2 genes in each patient with chromosomal copy number abnormalities (CNAs) found in EPCs, and also with clinical stage and disease severity, in order to elucidate the pathogenic information that the profiles hold. Conclusions: The genomes of EPCs display ranges of overlap with tumor cells in MM, evidenced by gene expression profiles with varying similarity to those found in MM tumor cells. More importantly, MM EPC gene expression profiles, in contrast to normal endothelial cells, contain cancer biomarker genes in tumors not yet associated with MM. Results strongly support the concept that EPCs are an integral part of the neoplastic process in MM.

scholarly journals Age-Related Modulation of the Effects of Obesity on Gene Expression Profiles of Mouse Bone Marrow and Epididymal Adipocytes

PLoS ONE ◽  
2013 ◽  
Vol 8 (8) ◽  
pp. e72367 ◽  
Author(s):  
Li-Fen Liu ◽  
Wen-Jun Shen ◽  
Masami Ueno ◽  
Shailja Patel ◽  
Salman Azhar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Mouse Bone Marrow ◽  
Age Related

scholarly journals TGFβ1-Induced Differentiation of Human Bone Marrow-Derived MSCs Is Mediated by Changes to the Actin Cytoskeleton

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Mona Elsafadi ◽  
Muthurangan Manikandan ◽  
Sami Almalki ◽  
Mohammad Mobarak ◽  
Muhammad Atteya ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Actin Cytoskeleton ◽  
Expression Profiles ◽  
Adipogenic Differentiation ◽  
Gene Expression Profiles ◽  
Cell Types ◽  
Cytochalasin D ◽  
Human Bone ◽  
Human Bone Marrow

TGFβ is a potent regulator of several biological functions in many cell types, but its role in the differentiation of human bone marrow-derived skeletal stem cells (hMSCs) is currently poorly understood. In the present study, we demonstrate that a single dose of TGFβ1 prior to induction of osteogenic or adipogenic differentiation results in increased mineralized matrix or increased numbers of lipid-filled mature adipocytes, respectively. To identify the mechanisms underlying this TGFβ-mediated enhancement of lineage commitment, we compared the gene expression profiles of TGFβ1-treated hMSC cultures using DNA microarrays. In total, 1932 genes were upregulated, and 1298 genes were downregulated. Bioinformatics analysis revealed that TGFβl treatment was associated with an enrichment of genes in the skeletal and extracellular matrix categories and the regulation of the actin cytoskeleton. To investigate further, we examined the actin cytoskeleton following treatment with TGFβ1 and/or cytochalasin D. Interestingly, cytochalasin D treatment of hMSCs enhanced adipogenic differentiation but inhibited osteogenic differentiation. Global gene expression profiling revealed a significant enrichment of pathways related to osteogenesis and adipogenesis and of genes regulated by both TGFβ1 and cytochalasin D. Our study demonstrates that TGFβ1 enhances hMSC commitment to either the osteogenic or adipogenic lineages by reorganizing the actin cytoskeleton.

scholarly journals Cryopreservation Preserves Cell-Type Composition and Gene Expression Profiles in Bone Marrow Aspirates From Multiple Myeloma Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Duojiao Chen ◽  
Mohammad I. Abu Zaid ◽  
Jill L. Reiter ◽  
Magdalena Czader ◽  
Lin Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Single Cell ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cell Type ◽  
Myeloma Cells ◽  
Freeze Thaw ◽  
Single Cell Rna Sequencing

Single-cell RNA sequencing reveals gene expression differences between individual cells and also identifies different cell populations that are present in the bulk starting material. To obtain an accurate assessment of patient samples, single-cell suspensions need to be generated as soon as possible once the tissue or sample has been collected. However, this requirement poses logistical challenges for experimental designs involving multiple samples from the same subject since these samples would ideally be processed at the same time to minimize technical variation in data analysis. Although cryopreservation has been shown to largely preserve the transcriptome, it is unclear whether the freeze-thaw process might alter gene expression profiles in a cell-type specific manner or whether changes in cell-type proportions might also occur. To address these questions in the context of multiple myeloma clinical studies, we performed single-cell RNA sequencing (scRNA-seq) to compare fresh and frozen cells isolated from bone marrow aspirates of six multiple myeloma patients, analyzing both myeloma cells (CD138+) and cells constituting the microenvironment (CD138−). We found that cryopreservation using 90% fetal calf serum and 10% dimethyl sulfoxide resulted in highly consistent gene expression profiles when comparing fresh and frozen samples from the same patient for both CD138+ myeloma cells (R ≥ 0.96) and for CD138– cells (R ≥ 0.9). We also demonstrate that CD138– cell-type proportions showed minimal alterations, which were mainly related to small differences in immune cell subtype sensitivity to the freeze-thaw procedures. Therefore, when processing fresh multiple myeloma samples is not feasible, cryopreservation is a useful option in single-cell profiling studies.

scholarly journals Classify Hyperdiploidy Status of Multiple Myeloma Patients Using Gene Expression Profiles

PLoS ONE ◽  
2013 ◽  
Vol 8 (3) ◽  
pp. e58809 ◽  
Author(s):  
Yingxiang Li ◽  
Xujun Wang ◽  
Haiyang Zheng ◽  
Chengyang Wang ◽  
Stéphane Minvielle ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Expression Profiles ◽  
Gene Expression Profiles

Effect of cell source and osteoblast differentiation on gene expression profiles of mesenchymal stem cells derived from bone marrow or adipose tissue

2019 ◽  
Vol 120 (7) ◽  
pp. 11842-11852 ◽  
Author(s):  
Simone Ortiz Moura Fideles ◽  
Adriana Cassia Ortiz ◽  
Amanda Freire Assis ◽  
Max Jordan Duarte ◽  
Fabiola Singaretti Oliveira ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Adipose Tissue ◽  
Osteoblast Differentiation ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cell Source

scholarly journals Maturation-associated gene expression profiles during normal human bone marrow erythropoiesis

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Fabiana V. Mello ◽  
Marcelo G. P. Land ◽  
Elaine. S. Costa ◽  
Cristina Teodósio ◽  
María-Luz Sanchez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Normal Human ◽  
Normal Human Bone Marrow

Interaction of Stem Cells and Their Niche: Behavior and Gene Expression Profiles of CD34+/CD38− Cells upon Co-Cultivation with AFT024.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1281-1281
Author(s):  
Wolfgang Wagner ◽  
Rainer Saffrich ◽  
Ute Wirkner ◽  
Volker Eckstein ◽  
Jonathon Blake ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Bone Marrow ◽  
Differential Gene Expression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Nuclear Antigen ◽  
Cd34 Cells ◽  
Differential Gene ◽  
The Impact

Abstract Cell-cell contact between stem cells and cellular determinants of the microenvironment plays an essential role in the regulation of self-renewal and differentiation. The stromal cell line derived from murine fetal liver (AFT024) has been shown to support maintenance of primitive human hematopoietic progenitor cells (HPC) in vitro. We have studied the interaction between HPC (defined as CD34+/CD38− umbilical cord blood cells) and AFT024 and the impact of co-cultivation on the behavior and gene expression of HPC. By time lapse microscopy the mobility and behavior of CD34+/CD38− cells were monitored. Approximately 30% of the CD34+/CD38− cells adhered to the cellular niche through an uropod. CD44 and CD34 were co-localized at the site of contact. Gene expression profiles of CD34+/CD38− cells were then compared upon co-cultivation either with or without AFT024. After cultivation for 16h, 20h, 48h or 72h the HPC were separated form the feeder layer cells by a second FAC-Sort. Differential gene expression was analyzed using our Human Genome cDNA Microarray of over 51,145 ESTs. Among the genes with the highest up-regulation in contact with AFT024 were several genes involved in cell adhesion, proliferation and DNA-modification including tubulin genes, ezrin, complement component 1 q subcomponent 1 (C1QR1), proto-oncogene proteins c-fos and v-fos, proliferating cell nuclear antigen (PCNA), HLA-DR, gamma-glutamyl hydrolase (GGH), minichromosome maintenance deficient 6 (MCM6), uracil-DNA glycolase (UNG) and DNA-methyltransferase 1 (DNMT1). In contrast, genes that were down-regulated after contact with AFT024 included collagenase type iv (MMP2), elastin (ELN) and hemoglobin genes. Differential expression of six genes was confirmed by RT-PCR. Other authors have reported on the differential gene expression profiles of CD34+ cells derived from the bone marrow versus those from G-CSF mobilized blood. As CD34+ cells from the bone marrow might represent cells exposed to the natural HPC niche we have then compared our findings with these experiments. In these comparisons we identified several overlapping genes that are involved in regulation of cell cycle and DNA repair including PCNA, DNMT1, MCM6, MCM2, CDC28 protein kinase regulatory subunit 1B (CKS1B), Topoisomerase II (TOP2a), DNA Ligase 1 (LIG1) and DNA mismatch repair protein MLH1. All these genes were up-regulated among CD34+/CD38− cells upon co-culture with AFT024, as well as among CD34+ cells derived from the bone marrow versus those from peripheral blood. Our studies support the hypothesis that intimate contact and adhesive interaction of HPC with their niche profoundly influenced their proliferative potential and their differentiation program.

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