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Fibronectin Binding Is Required for Acquisition of Mesenchymal/Endothelial Differentiation Potential in Human Circulating Monocytes  [PDF]
Noriyuki Seta,Yuka Okazaki,Keisuke Izumi,Hiroshi Miyazaki,Takashi Kato,Masataka Kuwana
Journal of Immunology Research , 2012, DOI: 10.1155/2012/820827
Abstract: We previously reported monocyte-derived multipotential cells (MOMCs), which include progenitors capable of differentiating into a variety of mesenchymal cells and endothelial cells. In vitro generation of MOMCs from circulating CD14+ monocytes requires their binding to extracellular matrix (ECM) protein and exposure to soluble factor(s) derived from circulating CD14- cells. Here, we investigated the molecular factors involved in MOMC generation by examining the binding of monocytes to ECM proteins. We found that MOMCs were obtained on the fibronectin, but not on type I collagen, laminin, or poly-L-lysine. MOMC generation was followed by changes in the expression profiles of transcription factors and was completely inhibited by either anti-α5 integrin antibody or a synthetic peptide that competed with the RGD domain for the β1-integrin binding site. These results indicate that acquisition of the multidifferentiation potential by circulating monocytes depends on their binding to the RGD domain of fibronectin via cell-surface α5β1 integrin. 1. Introduction Circulating CD14+ monocytes originate from hematopoietic stem cells in the bone marrow and are heterogeneous in terms of their surface markers, phagocytic capacity, and differentiation potentials [1]. Until recently, it was believed that the differentiation potential of monocytes was restricted to cells that function as phagocytes and/or antigen-presenting cells, including macrophages, dendritic cells, and osteoclasts, but recent accumulating evidence indicates that circulating monocytes have the potential to differentiate into a variety of cell types other than phagocytes [2–6]. We recently identified a peripheral blood-derived cell population that has a fibroblast-like morphology in culture and a unique phenotype positive for CD14, CD45, CD34, and type I collagen (collagen (I)) [7]. These cells originate from circulating CD14+ monocytes and include primitive cells that can differentiate into cells with morphologic, phenotypic, and functional features of several distinct mesenchymal cell types, including bone, cartilage, fat, and skeletal and cardiac muscle, as well as neurons and endothelium; thus, they are termed monocyte-derived multipotential cells (MOMCs) [7–10]. It is thus plausible that circulating monocytes are involved in tissue remodelling and regeneration through MOMC differentiation under physiologic and pathogenic conditions in vivo. MOMCs are obtained in 7-day cultures of peripheral blood mononuclear cells (PBMCs) on fibronectin-coated plastic plates with 10% fetal bovine serum (FBS) as
Differentiation Potential of CD14+ Monocytes into Myofibroblasts in Patients with Systemic Sclerosis  [PDF]
Nadine Binai, Steven O'Reilly, Bridget Griffiths, Jacob M. van Laar, Thomas Hügle
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0033508
Abstract: Background Circulating monocytes are a highly plastic and functionally heterogeneic cell type with an activated phenotype in patients with systemic sclerosis (SSc). CD14+ monocytes have the potential to differentiate into extra-cellular matrix (ECM) producing cells, possibly participating in fibrogenesis. Aim To study the effect of GM-CSF, IL-4 and endothelin -1 (ET-1) alone or in combination on monocyte differentiation into myofibroblasts. Methods CD14+ cells were isolated from peripheral blood from 14 SSc patients and healthy controls by positive selection and incubated with different combinations of GM-CSF, IL-4 and ET-1 for 14 days. Type-1 collagen and α-SMA were detected by Western blot, qPCR and confocal microscopy. HLA-DR, CD11c and CD14 expression was analysed by flow cytometry. A collagen gel contraction assay was performed for functional myofibroblast assessment. Results GM-CSF both induced collagen and α-SMA expression after 14 days. ET-1 further increased GM-CSF-induced collagen expression in a dose dependent manner up to 30-fold. IL-4/GM-CSF combination leads to a more DC-like phenotype of monocytes associated with reduced collagen and α-SMA expression compared to GM-CSF alone. Collagen and α-SMA expression was higher in monocytes from SSc patients and monocytes were more prone to obtain a spindle form. In contrast to controls, ET-1 and IL-4 alone were sufficient to induce α-SMA expression in monocytes from SSc patients. Despite the induction of α-SMA expression, monocyte-derived myofibroblasts only had a moderate capability of contraction in functional analyses. Conclusion SSc monocytes display increased maturation towards myofibroblasts demonstrated by their phenotype and α-SMA expression when compared to monocytes from healthy controls, however only with minor functional contraction properties.
Adipocytokines in Atherothrombosis: Focus on Platelets and Vascular Smooth Muscle Cells  [PDF]
Giovanni Anfossi,Isabella Russo,Gabriella Doronzo,Alice Pomero,Mariella Trovati
Mediators of Inflammation , 2010, DOI: 10.1155/2010/174341
Abstract: Visceral obesity is a relevant pathological condition closely associated with high risk of atherosclerotic vascular disease including myocardial infarction and stroke. The increased vascular risk is related also to peculiar dysfunction in the endocrine activity of adipose tissue responsible of vascular impairment (including endothelial dysfunction), prothrombotic tendency, and low-grade chronic inflammation. In particular, increased synthesis and release of different cytokines, including interleukins and tumor necrosis factor- (TNF- ), and adipokines—such as leptin—have been reported as associated with future cardiovascular events. Since vascular cell dysfunction plays a major role in the atherothrombotic complications in central obesity, this paper aims at focusing, in particular, on the relationship between platelets and vascular smooth muscle cells, and the impaired secretory pattern of adipose tissue. 1. Introduction Subjects affected by central obesity (i.e., by intra-abdominal fat excess) are characterized by insulin resistance, metabolic disorders, and vascular abnormalities which cooperate to induce high cardiovascular risk [1–3]. The so-called “metabolic syndrome”, defined on the basis of a combination of central obesity, glucose intolerance, atherogenic dyslipidemia, and arterial hypertension [3, 4], is present in the large majority of these subjects. In central obesity, abnormalities in the extent and distribution of fat mass are associated with a peculiar dysfunction of adipose tissue, responsible—together with the insulin resistance—of alterations of vascular function (including endothelial dysfunction), pro-thrombotic tendency, low-grade chronic inflammation, and oxidative stress: these defects, frequently associated as a cluster, represent the main pathogenetic link between obesity and the increased risk of athero-thrombotic events [5–7]. Omental adipose tissue, which comprises both adipocytes and a stromovascular cell fraction, is not an inert lipid storage site, but a dynamic endocrine organ able to synthesize and secrete many bioactive peptides—collectively named “adipocytokines”—deeply involved in the metabolic, vascular, and immunological homeostasis by paracrine and endocrine mechanisms [2, 6, 8–10]. Some molecules, directly synthesized by adipocytes and called “adipokines” (i) control energy balance and appetite, and influence insulin sensitivity via endocrine mechanisms, and (ii) modulate adipocyte size/number and angiogenesis via paracrine mechanisms, thus exerting a major role in the regulation of fat mass [10, 11]. Furthermore,
Ly6C- Monocytes Regulate Parasite-Induced Liver Inflammation by Inducing the Differentiation of Pathogenic Ly6C+ Monocytes into Macrophages  [PDF]
Yannick Morias?,Chloé Abels?,Damya Laoui?,Eva Van Overmeire?,Martin Guilliams?,Elio Schouppe?,Frank Tacke?,Carlie J. deVries?,Patrick De Baetselier?,Alain Beschin
PLOS Pathogens , 2015, DOI: 10.1371/journal.ppat.1004873
Abstract: Monocytes consist of two well-defined subsets, the Ly6C+ and Ly6C– monocytes. Both CD11b+ myeloid cells populations have been proposed to infiltrate tissues during inflammation. While infiltration of Ly6C+ monocytes is an established pathogenic factor during hepatic inflammation, the role of Ly6C– monocytes remains elusive. Mice suffering experimental African trypanosome infection die from systemic inflammatory response syndrome (SIRS) that is initiated by phagocytosis of parasites by liver myeloid cells and culminates in apoptosis/necrosis of liver myeloid and parenchymal cells that reduces host survival. C57BL/6 mice are considered as trypanotolerant to Trypanosoma congolense infection. We have reported that in these animals, IL-10, produced among others by myeloid cells, limits the liver damage caused by pathogenic TNF-producing Ly6C+ monocytes, ensuring prolonged survival. Here, the heterogeneity and dynamics of liver myeloid cells in T. congolense-infected C57/BL6 mice was further dissected. Moreover, the contribution of Ly6C– monocytes to trypanotolerance was investigated. By using FACS analysis and adoptive transfer experiments, we found that the accumulation of Ly6C– monocytes and macrophages in the liver of infected mice coincided with a drop in the pool of Ly6C+ monocytes. Pathogenic TNF mainly originated from Ly6C+ monocytes while Ly6C– monocytes and macrophages were major and equipotent sources of IL-10 within myeloid cells. Moreover, Nr4a1 (Nur77) transcription factor-dependent Ly6C– monocytes exhibited IL-10-dependent and cell contact-dependent regulatory properties contributing to trypanotolerance by suppressing the production of TNF by Ly6C+ monocytes and by promoting the differentiation of the latter cells into macrophages. Thus, Ly6C– monocytes can dampen liver damage caused by an extensive Ly6C+ monocyte-associated inflammatory immune response in T. congolense trypanotolerant animals. In a more general context, Ly6C– or Ly6C+ monocyte targeting may represent a therapeutic approach in liver pathogenicity induced by chronic infection.
Transforming growth factor-β and smooth muscle differentiation  [cached]
Xia Guo,Shi-You Chen
World Journal of Biological Chemistry , 2012, DOI: 10.4331/wjbc.v3.i3.41
Abstract: Transforming growth factor (TGF)-β family members are multifunctional cytokines regulating diverse cellular functions such as growth, adhesion, migration, apoptosis, and differentiation. TGF-βs elicit their effects via specific type I and type II serine/threonine kinase receptors and intracellular Smad transcription factors. Knockout mouse models for the different components of the TGF-β signaling pathway have revealed their critical roles in smooth muscle cell (SMC) differentiation. Genetic studies in humans have linked mutations in these signaling components to specific cardiovascular disorders such as aorta aneurysm and congenital heart diseases due to SMC defects. In this review, the current understanding of TGF-β function in SMC differentiation is highlighted, and the role of TGF-β signaling in SMC-related diseases is discussed.
Monocytes/macrophages express chemokine receptor CCR9 in rheumatoid arthritis and CCL25 stimulates their differentiation
Caroline Schmutz, Alison Cartwright, Helen Williams, Oliver Haworth, John HH Williams, Andrew Filer, Mike Salmon, Christopher D Buckley, Jim Middleton
Arthritis Research & Therapy , 2010, DOI: 10.1186/ar3120
Abstract: CCR9 expression on PB monocytes/macrophages was analysed by flow cytometry and in synovium by immunofluorescence. Chemokine receptor CCR9 mRNA expression was examined in RA and non-RA synovium, monocytes/macrophages from PB and synovial fluid (SF) of RA patients and PB of healthy donors using the reverse transcription polymerase chain reaction (RT-PCR). Monocyte differentiation and chemotaxis to chemokine ligand 25 (CCL25)/TECK were used to study CCR9 function.CCR9 was expressed by PB monocytes/macrophages in RA and healthy donors, and increased in RA. In RA and non-RA synovia, CCR9 co-localised with cluster of differentiation 14+ (CD14+) and cluster of differentiation 68+ (CD68+) macrophages, and was more abundant in RA synovium. CCR9 mRNA was detected in the synovia of all RA patients and in some non-RA controls, and monocytes/macrophages from PB and SF of RA and healthy controls. CCL25 was detected in RA and non-RA synovia where it co-localised with CD14+ and CD68+ cells. Tumour necrosis factor alpha (TNFα) increased CCR9 expression on human acute monocytic leukemia cell line THP-1 monocytic cells. CCL25 induced a stronger monocyte differentiation in RA compared to healthy donors. CCL25 induced significant chemotaxis of PB monocytes but not consistently among individuals.CCR9 expression by monocytes is increased in RA. CCL25 may be involved in the differentiation of monocytes to macrophages particularly in RA.Rheumatoid arthritis (RA) is a chronic inflammatory disease resulting in the accumulation of macrophages, T cells and B cells within the synovium. The accumulation of these cells is involved in the development of inflammation, joint destruction and pain [1]. Monocytes migrate from the blood across the walls of synovial blood vessels and differentiate into macrophages. The clinical importance of monocytes/macrophages is revealed by the correlation between their number, disease activity and radiographic progression [2-4] and by the beneficial effect of therapi
Osteoclastic differentiation of mouse and human monocytes in a plasma clot/biphasic calcium phosphate microparticles composite  [PDF]
CC Mouline,D Quincey,J-P Laugier,GF Carle
European Cells and Materials (ECM) , 2010,
Abstract: We recently demonstrated that blood clotted around biphasic calcium phosphate (BCP) microparticles constituted a composite biomaterial that could be used for bone defect filling. In addition, we showed that mononuclear cells, i.e. monocytes and lymphocytes, play a central role in the osteogenic effect of this biomaterial. Hypothesizing that osteoclast progenitors could participate to the pro-osteogenic effect of mononuclear cells we observed previously, we focus on this population through the study of mouse monocyte/macrophage cells (RAW264.7 cell line), as well as human pre-osteoclastic cells derived from mononuclear hematopoietic progenitor cells (monocytes-enriched fraction from peripheral blood). Using monocyte-derived osteoclast progenitors cultured within plasma clot/BCP microparticles composite, we aimed in the present report at the elucidation of transcriptional profiles of genes related to osteoclastogenesis and to bone remodelling. For both human and mouse monocytes, real-time PCR experiments demonstrated that plasma clot/BCP scaffold potentiated the expression of marker genes of the osteoclast differentiation such as Nfactc1, Jdp2, Fra2, Tracp and Ctsk. By contrast, Mmp9 was induced in mouse but not in human cells, and Ctr expression was down regulated for both species. In addition, for both mouse and human precursors, osteoclastic differentiation was associated with a strong stimulation of VegfC and Sdf1 genes expression. At last, using field-emission scanning electron microscopy analysis, we observed the interactions between human monocytes and BCP microparticles. As a whole, we demonstrated that plasma clot/BCP microparticles composite provided monocytes with a suitable microenvironment allowing their osteoclastic differentiation, together with the production of pro-angiogenic and chemoattractant factors.
Gene induction during differentiation of human monocytes into dendritic cells: an integrated study at the RNA and protein levels  [PDF]
C. Angénieux,D. Fricker,J. M. Strub,S. Luche,H. Bausinger,J. P. Cazenave,A. Van Dorsselaer,D. Hanau,H. de la Salle,T. Rabilloud
Quantitative Biology , 2006, DOI: 10.1007/s101420100037
Abstract: Changes in gene expression occurring during differentiation of human monocytes into dendritic cells were studied at the RNA and protein levels. These studies showed the induction of several gene classes corresponding to various biological functions. These functions encompass antigen processing and presentation, cytoskeleton, cell signalling and signal transduction, but also an increase in mitochondrial function and in the protein synthesis machinery, including some, but not all, chaperones. These changes put in perspective the events occurring during this differentiation process. On a more technical point, it appears that the studies carried out at the RNA and protein levels are highly complementary.
In-vitro differentiation of rat peripheral blood monocytes into insulin-producing cells by rat pancreatic extract
Tanhaye Kalate Sabz F,Farokhi F,Delirezh N,Chapari H
Tehran University Medical Journal , 2011,
Abstract: Background: Cell-therapy provides a promising alternative for the treatment of type 1 diabetes. Monocytes which have a reprogramming or differentiation potential and are more available than any other types of stem cells, have been recognized as candidates for such investigations. The aim of the present study was to evaluate the differentiation potential of rat peripheral blood monocytes into insulin-producing cells by the use of rat pancreatic extract (2 days after a 60% pancreatectomy). Methods: Rat peripheral blood monocytes were isolated and cultured. Adherent monocytes were induced to differentiate into programmable cells in RPMI supplemented by 10% FCS, β-mercaptoetanol, M-CSF and IL-3 for six days. The dedifferentiated cells were analyzed by invert microscopy. Cultures of Programmable Cells of Monocytic Origin (PCMOs) were continued in RPMI, containing 10% FBS, pancreatic extract and 5 mmol/L glucose for 15 days. The medium was replaced every three days. At the end of the protocol, insulin and c-peptide excreted by the differentiated cells were tested by radioimmunoassay on days 6, 14, and 21. In order to verify insulin production in the cells, dithizone-staining, which is a method for insulin identification, was employed. Results: The results showed that the cells cultured in rat pancreatic extract secreted insulin and c-peptide relative to the control group. Dithizone-staining was positive in the aforesaid cells (P<0/05). Conclusion: The results of the current study showed that pancreatic extract treatment can differentiate rat peripheral blood monocytes into insulin-producing cells which can be regarded as a potential source for the treatment of diabetes.
Platelet-Derived Stromal Cell-Derived Factor-1 Is Required for the Transformation of Circulating Monocytes into Multipotential Cells  [PDF]
Noriyuki Seta, Yuka Okazaki, Hiroshi Miyazaki, Takashi Kato, Masataka Kuwana
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074246
Abstract: Background We previously described a primitive cell population derived from human circulating CD14+ monocytes, named monocyte-derived multipotential cells (MOMCs), which are capable of differentiating into mesenchymal and endothelial lineages. To generate MOMCs in vitro, monocytes are required to bind to fibronectin and be exposed to soluble factor(s) derived from circulating CD14? cells. The present study was conducted to identify factors that induce MOMC differentiation. Methods We cultured CD14+ monocytes on fibronectin in the presence or absence of platelets, CD14? peripheral blood mononuclear cells, platelet-conditioned medium, or candidate MOMC differentiation factors. The transformation of monocytes into MOMCs was assessed by the presence of spindle-shaped adherent cells, CD34 expression, and the potential to differentiate in vitro into mesenchymal and endothelial lineages. Results The presence of platelets or platelet-conditioned medium was required to generate MOMCs from monocytes. A screening of candidate platelet-derived soluble factors identified stromal cell-derived factor (SDF)-1 as a requirement for generating MOMCs. Blocking an interaction between SDF-1 and its receptor CXCR4 inhibited MOMC generation, further confirming SDF-1′s critical role in this process. Finally, circulating MOMC precursors were found to reside in the CD14+CXCR4high cell population. Conclusion The interaction of SDF-1 with CXCR4 is essential for the transformation of circulating monocytes into MOMCs.
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