Paracrine regulation of megakaryo/thrombopoiesis by macrophages

D’Atri, Lina Paola; Pozner, Raúl; Nahmod, Karen; Landoni, Verónica Inés; Isturiz, Martı́n A.; Negrotto, Soledad; Schattner, Mirta

doi:10.1016/j.exphem.2011.03.009

Cited by 10 publications

(13 citation statements)

References 45 publications

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“…On the other hand, we suspect that the high proliferative responses (i.e., increased TNC counts) in the presence of GM-CSF even while CFU-MK progenitor growth is inhibited is most likely due to GM-CSF supporting the growth of other hematopoietic cell lineages such as granulocytes and monocytes (4). As noted by D'Atri et al (8), the inhibitory effect of GM-CSF on CD41ϩ cells is a result of a switch of CD34ϩ cells differentiation toward the monocytic lineage. The finding that CSFR2B is also expressed on platelets sug- gests that GM-CSF might have a biological role in modulating platelet function.…”

Section: Discussionmentioning

confidence: 98%

“…Adiponectin is a well-documented regulator of a number of metabolic processes (19); it is expressed in adult BM (34) and in 2007 identified as a novel hematopoietic stem cell growth factor (9). Adiponectin levels inversely correlate with body fat content in adults (8,33), and in individuals with hematological disorders (1,23). Adiponectin suppresses BM granulocyte/macrophage colony formation (7) and is secreted by adipocytes, as well as by a number of other cell types (3,7,16,21,24,35).…”

Section: Discussionmentioning

confidence: 99%

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Expression of plasma membrane receptor genes during megakaryocyte development

Sun

Wang

Latchman

et al. 2013

Physiological Genomics

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karyocyte (MK) development is critically informed by plasma membrane-localized receptors that integrate a multiplicity of environmental cues. Given that the current understanding about receptors and ligands involved in megakaryocytopoiesis is based on single targets, we performed a genome-wide search to identify a plasma membrane receptome for developing MKs. We identified 40 transmembrane receptor genes as being upregulated during MK development. Seven of the 40 receptorassociated genes were selected to validate the dataset. These genes included: interleukin-9 receptor (IL9R), transforming growth factor, ␤ receptor II (TGFBR2), interleukin-4 receptor (IL4R), colony stimulating factor-2 receptor-beta (CSFR2B), adiponectin receptor (ADIPOR2), thrombin receptor (F2R), and interleukin-21 receptor (IL21R). RNA and protein analyses confirmed their expression in primary human MKs. Matched ligands to IL9R, TGFBR2, IL4R, CSFR2B, and ADIPOR2 affected megakaryocytopoiesis. IL9 was unique in its ability to increase the number of MKs formed. In contrast, MK colony formation was inhibited by adiponectin, TGF-␤, IL4, and GM-CSF. The thrombin-F2R axis affected platelet function, but not MK development, while IL21 had no apparent detectable effects. ADP-induced platelet aggregation was suppressed by IL9, TGF-␤, IL4, and adiponectin. Overall, six of seven of the plasma membrane receptors were confirmed to have functional roles in MK and platelet biology. Also, results show for the first time that adiponectin plays a regulatory role in MK development. Together these data support a strong likelihood that the 40 transmembrane genes identified as being upregulated during MK development will be an important resource to the research community for deciphering the complex repertoire of environmental cues regulating megakaryocytopoiesis and/or platelet function.receptors; megakaryocytopoiesis; thrombocytopoiesis; hematopoiesis; microarray MEGAKARYOCYTOPOIESIS INVOLVES the proliferation and differentiation of hematopoietic stem cells to form megakaryocyte (MK) progenitors that undergo a maturation process that culminates in a release of ϳ10 11 platelets per day into the blood circulation (31). This process is tightly regulated by a number of factors, which include extracellular cues such as cytokines, cell-to-cell interactions, and cell-to-extracellular matrix interactions. Among cytokines that are known to act as important extracellular regulators of megakaryocytopoiesis is the main physiological stimulator of this specific cell-lineage commitment, thrombopoietin (TPO) (17). Additionally, interleukin 3 (IL3), interleukin 6 (IL6), interleukin 11 (IL11), stem cell factor (SCF), and fms-like tyrosine kinase 3 ligand act as positive regulators of MK development (17, 31). There are also several cytokines such as transforming growth factor-beta (TGF-␤), platelet factor 4, and interleukin 4 (IL4) that are documented as negative regulators of MK development (31).The importance of megakaryocytopoiesis and platelet biogenesis is apparent; morbidit...

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Expression of plasma membrane receptor genes during megakaryocyte development

Sun

Wang

Latchman

et al. 2013

Physiological Genomics

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“…Isolation of CD34+ cells from human umbilical cord blood was performed using a magnetic cell‐sorting system (Miltenyi Biotec, Gladbach, Germany) as previously described [18]. The purity of the cell suspension was determined by flow cytometry and typically ranged from 95% to 99%.…”

Section: Methodsmentioning

confidence: 99%

Expression and functionality of type I interferon receptor in the megakaryocytic lineage

Negrotto

Giusti

Lapponi

et al. 2011

Journal of Thrombosis and Haemostasis

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To cite this article: Negrotto S, de Giusti CJ, Lapponi MJ, Etulain J, Rivadeneyra L, Pozner RG, Gomez RM, Schattner M. Expression and functionality of type I interferon receptor in the megakaryocytic lineage. J Thromb Haemost 2011; 9: 2477-85.Summary. Background: Type I interferons (IFN-I) negatively regulate megakaryo/thrombopoiesis. However, expression of the IFN-I receptor (IFNAR) in the megakaryocytic lineage is poorly characterized. Objectives: To study the expression and functionality of IFNAR in the megakaryocytic lineage. Methods and results: Although IFNAR mRNA was found in every cell type studied, its protein expression showed differences between them. According to flow cytometry and immunofluorescence, IFNAR1 was observed in Meg-01, Dami, CD34+ cells and megakaryocytes, but not in proplatelets or platelets. Immunoblotting assays showed that IFNAR1 and IFNAR2 were highly expressed in all cell types, except in platelets where it was barely detectable. Regarding IFNAR1, 130-and 90-kDa bands were detected in Meg-01 and Dami, whereas 130-and 60-kDa bands were found in CD34+ cells and megakaryocytes. Activation of megakaryocytic IFNAR by IFN-b induced pSTAT1/2 and upregulated the antiviral genes IRF7 and MXA. The latter response was completely suppressed by IFNAR blockade. In contrast, the low levels of IFNAR in platelets were not functional as pSTAT1/2, aggregation and Pselectin expression were not induced by IFN-I. In addition, megakaryocytes increased IFN-I transcript levels and produced IFN-b upon stimulation with PolyI:C, a synthetic dsRNA that mimics viral infection. Conclusions: Early progenitors and mature megakaryocytes, but not platelets, express functional IFNAR and synthetize/release IFN-b, revealing not only that megakaryo/thrombopoiesis regulation by IFN-I is associated with a specific interaction with its receptor, but also that megakaryocytes may play a role in the antiviral defense by being both IFN producers and responders.

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“…Abnormal megakaryocyte morphology has been noted in multiple reports (example in Abgrall 1992),[28] and thrombopoietin, a potent stimulus for thrombopoiesis that is negatively regulated by platelet uptake from the circulation and therefore normally rises with platelet decline, is elevated in HIV-infected individuals yet is not correlated with platelet number. [31] It has been previously reported that resting bone marrow macrophages release soluble cytokines that promote megakaryocyte growth and platelet release while LPS-activated macrophages inhibit megakaryocyte development and growth,[32] but a similar inhibitory role for activated or infected bone marrow macrophages in the context of HIV has yet to be explored.…”

Section: Thrombocytopenia In Hivmentioning

confidence: 99%

HIV and SIV associated thrombocytopenia: an expanding role for platelets in the pathogenesis of HIV

Pate

Mankowski

2011

Drug Discovery Today: Disease Mechanisms

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Thrombocytopenia is common in HIV and SIV infection, and is often associated with disease progression. HIV and SIV-associated thrombocytopenia arise through multiple mechanisms, including decreased platelet production, increased platelet destruction due to HIV-mimetic anti-platelet antibodies, and increased use of activated platelets. Activated platelets have the potential to contribute to the pathogenesis of HIV and SIV by interacting directly with inflammatory cells and endothelium and by releasing soluble immunomodulatory cytokines.

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Paracrine regulation of megakaryo/thrombopoiesis by macrophages

Cited by 10 publications

References 45 publications

Expression of plasma membrane receptor genes during megakaryocyte development

Expression of plasma membrane receptor genes during megakaryocyte development

Expression and functionality of type I interferon receptor in the megakaryocytic lineage

HIV and SIV associated thrombocytopenia: an expanding role for platelets in the pathogenesis of HIV

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