Thrombospondin, a negative modulator of megakaryocytopoiesis

Chen, Yuan Zhong; Incardona, Francesca; Legrand, Chantal; Momeux, Laurence; Caen, Jacques P.; Han, Zhong Chao

doi:10.1016/s0022-2143(97)90144-x

Cited by 18 publications

(9 citation statements)

References 27 publications

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“…Beta 1 integrin D U33880 ‫21.5מ‬ 0.0021 1.0000 1.0000 TPO up-regulates adhesion of hematopoetic progenitors to fibronectin through activation of integrin alpha4beta1 and alpha5beta1 (Gotoh et al 1997). Sp4 transcription factor X68561 ‫60.5מ‬ 0.0030 1.0000 1.0000 Sp4 not well characterized but closely related to Sp1 (Suske 1999), TPO activates several Sp1-dependent genes during megakaryopoiesis (Wang et al 1999 (Streit et al 1999), close relative thrombospondin 1 is negative regulator of megakaryopoiesis (Chen et al 1997;Touhami et al 1997 (Marlton et al 1995;Mancini et al 2000), CML/ALL translocations identified in 10q (Kagan et al 1989;Aguiar et al 1997;Salvati et al 1999 (Melnick et al 1999), isochromosomes on 17q common (Fioretos et al 1999) Biglycan J04599 ‫71.4מ‬ 0.2119 1.0000 1.0000 Xq28 Translocation found in AML (Weis et al 1985), common in ALL (Stern 1996 Dataset from Golub et al (1999).…”

Section: Discussionmentioning

confidence: 99%

An Efficient and Robust Statistical Modeling Approach to Discover Differentially Expressed Genes Using Genomic Expression Profiles

Thomas¹,

Olson²,

Tapscott³

et al. 2001

Genome Res.

286

192

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We have developed a statistical regression modeling approach to discover genes that are differentially expressed between two predefined sample groups in DNA microarray experiments. Our model is based on well-defined assumptions, uses rigorous and well-characterized statistical measures, and accounts for the heterogeneity and genomic complexity of the data. In contrast to cluster analysis, which attempts to define groups of genes and/or samples that share common overall expression profiles, our modeling approach uses known sample group membership to focus on expression profiles of individual genes in a sensitive and robust manner. Further, this approach can be used to test statistical hypotheses about gene expression. To demonstrate this methodology, we compared the expression profiles of 11 acute myeloid leukemia (AML) and 27 acute lymphoblastic leukemia (ALL) samples from a previous study ) and found 141 genes differentially expressed between AML and ALL with a 1% significance at the genomic level. Using this modeling approach to compare different sample groups within the AML samples, we identified a group of genes whose expression profiles correlated with that of thrombopoietin and found that genes whose expression associated with AML treatment outcome lie in recurrent chromosomal locations. Our results are compared with those obtained using t-tests or Wilcoxon rank sum statistics.

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Section: Discussionmentioning

confidence: 99%

An Efficient and Robust Statistical Modeling Approach to Discover Differentially Expressed Genes Using Genomic Expression Profiles

Thomas¹,

Olson²,

Tapscott³

et al. 2001

Genome Res.

286

192

View full text Add to dashboard Cite

show abstract

“…Glypican-4 is found in HSCs (Siebertz et al, 1999) and loss of function mutations in glypican-3 result in perturbed hematopoiesis (Viviano et al, 2005). Furthermore, syndecan is a likely mediator of thrombospondin activity (Chen et al, 1997) during development of the HSC niche (Corless et al, 1992), with syndecan-1 and perlecan additionally involved in the mesenchymal stem cell niche (Chen et al, 2007b). Many of these HSPG-modulated activities have recently been reviewed (Nurcombe and Cool, 2007).…”

Section: Hspgs In the Hematopoietic Stem Cell Nichementioning

confidence: 99%

Heparan sulfate proteoglycans: A GAGgle of skeletal‐hematopoietic regulators

Rodgers

Antonio

Jacenko

2008

Developmental Dynamics

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This review summarizes our current understanding of the presence and function of heparan sulfate proteoglycans (HSPGs) in skeletal development and hematopoiesis. Although proteoglycans (PGs) comprise a large and diverse group of cell surface and matrix molecules, we chose to focus on HSPGs owing to their many proposed functions in skeletogenesis and hematopoiesis. Specifically, we discuss how HSPGs play predominant roles in establishing and regulating niches during skeleto-hematopoietic development by participating in distinct developmental processes such as patterning, compartmentalization, growth, differentiation, and maintenance of tissues. Special emphasis is placed on our novel hypothesis that mechanistically links endochondral skeletogenesis to the establishment of the hematopoietic stem cell (HSC) niche in the marrow. HSPGs may contribute to these developmental processes through their unique abilities to establish and mediate morphogen, growth factor, and cytokine gradients; facilitate signaling; provide structural stability to tissues; and act as molecular filters and barriers. Developmental TRIBUTE TO DR. ELIZABETH D. HAYDr. Elizabeth Dexter Hay, "Betty" to her friends, would often introduce her seminars on extracellular matrix (ECM) and epithelial-mesenchymal cell transformations by showing pictures of her cats asleep intertwined with a blanket. She would use this analogy to highlight the intimate association that exists between a cell and its ECM during development. She was a pioneer who brought forth the notion that the ECM is not just a static "stuffing between cells," but has interactive and instructive roles in development.Betty's contribution to the ECM field began with her seminal discoveries in the emerging field of electron microscopy. She worked with Keith Porter, George Palade, Don Fawcett, Susumo Ito, Jean-Paul Revel, and others to unravel the intricate microanatomy of the cell and its ECM. Once, when working with Jean-Paul Revel to extend autoradiography to the ultrastructural level, Betty noticed that tritiated proline was incorporated into collagen in the ECM outside of the cartilage cells. Betty went on to demonstrate that epithelial cells, as well as other non-fibroblastic cells, do secrete collagen. Moreover, in her descriptions of the development and structure of the various matrices, Betty brought forth the hypothesis that the ECM interacts with cells, and that through these interactions, the cells are instructed to modify their behavior. This notion was showcased in the "Epithelial-Mesenchymal Transformation Model" she proposed to describe the dramatic morphological transformations of epithelial cells suspended in collagen gels.Among her numerous scientific accomplishments, Betty can be considered a founder of the field of cell biology. Moreover, through her personal attributes and interactions with col- leagues and her protegees, Betty has set the standard for many a scientist. This review is a tribute to Betty, a friend, colleague, and mentor, and highlights our developing premi...

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“…It has been demonstrated that mice deficient in both TSP-1 and TSP-2 displayed a more rapid regeneration of thrombopoiesis after myelosuppression, 16 extending previous in vitro results that indicated that TSPs negatively regulate megakaryopoiesis. 17 Here, we cannot exclude that TSP-1 deficiency shortens platelet recovery under TPO stimulation. Nevertheless, we did not observe a further increase of megakaryocyte hyperplasia or thrombocytosis in Tsp-1-null TPO high mice compared with WT TPO high mice during disease progression.…”

Section: Resultsmentioning

confidence: 85%

Thrombospondin-1 is not the major activator of TGF-β1 in thrombopoietin-induced myelofibrosis

Evrard

Bluteau

Tulliez

et al. 2011

Blood

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Transforming growth factor-␤1 (TGF-␤1) is the most important cytokine involved in the promotion of myelofibrosis. Mechanisms leading to its local activation in the bone marrow environment remain unclear. As a recent study has highlighted the role of thrombospondin-1 (TSP-1) in platelet-derived TGF-␤1 activation, we investigated the role of TSP-1 in the TPO high murine model of myelofibrosis. Two groups of engrafted mice, WT TPO high and Tsp-1-null TPO high , were constituted. All mice developed a similar myeloproliferative syndrome and an increase in total TGF-␤1 levels in the plasma and in extracellular fluids of marrow and spleen. Surprisingly, we were able to detect the active form of TGF-␤1 in Tsp-1-null TPO high mice. Accordingly, these mice developed marrow and spleen fibrosis, with intriguingly a higher grade than in WT TPO high mice. Our results show that TSP-1 is not the major activator of TGF-␤1 in TPOinduced myelofibrosis, suggesting the contribution of another mechanism in the megakaryocyte/platelet compartment. IntroductionTransforming growth factor-␤1 (TGF-␤1) is a pleiotropic cytokine involved in normal tissue repair, and its sustained production induces fibrosis in numerous organs, 1 including myelofibrosis. 2 Mechanisms leading to in vivo TGF-␤1 activation (from inactive proforms) remain complex, 3 involving interactions with integrins, 4-6 thrombospondin-1 (TSP-1), 7 or shear forces. 8 In a murine model of myelofibrosis obtained by thrombopoietin (TPO) overexpression, 9 enhanced release of TGF-␤1 2 occurs mainly from megakaryocytes and, to a lesser extent, from monocytes. 10 Because both TGF-␤1 and TSP-1 are synthesized and stored in megakaryocyte ␣-granules, 11 abnormal and concomitant release of both molecules may hypothetically lead to pathologic local TGF-␤1 activation. As a recent study has highlighted the role of TSP-1 in platelet-derived TGF-␤1 activation, 12 we investigated the role of TSP-1 in TPO-induced myelofibrosis. MethodsWe used the TPO high murine model. All procedures were approved by the Institut Gustave Roussy ethics committee. Bone marrow (BM) cells from C57BL/6 wild-type (WT) or Tsp-1-null 13 male littermates were infected with a retrovirus encoding murine TPO 9 and engrafted into lethally irradiated WT or Tsp-1-null female hosts, respectively, leading to the following 2 engraftment combinations: WT/WT (ie, WT TPO high mice, n ϭ 22) and Tsp-1-null/Tsp-1-null (ie, Tsp-1-null TPO high mice, n ϭ 15). Lethally irradiated hosts were engrafted with 4 to 8 ϫ 10 6 cells in 2 independent experiments. Peripheral blood was analyzed every 4 weeks during 3 months using an automated blood counter calibrated for mouse blood (MS9, Melet Schloessing). Control mice included unmanipulated WT and Tsp-1-null mice. At weeks 8 and 12 after engraftment, mice were killed for histologic analysis. Reticulin fibers revealed by silver staining were quantified using ImageJ Version 1.42q software (National Institutes of Health). Microvascular density (MVD) was determined by CD34 staining. 14 TPO and TGF...

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Thrombospondin, a negative modulator of megakaryocytopoiesis

Cited by 18 publications

References 27 publications

An Efficient and Robust Statistical Modeling Approach to Discover Differentially Expressed Genes Using Genomic Expression Profiles

An Efficient and Robust Statistical Modeling Approach to Discover Differentially Expressed Genes Using Genomic Expression Profiles

Heparan sulfate proteoglycans: A GAGgle of skeletal‐hematopoietic regulators

Thrombospondin-1 is not the major activator of TGF-β1 in thrombopoietin-induced myelofibrosis

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