Article

The molecular mechanisms that control thrombopoiesis. J Clin Invest

Department of Medicine, Division of Hematology/Oncology, University of California, San Diego, California 92103-3931, USA.
Journal of Clinical Investigation (Impact Factor: 13.77). 01/2006; 115(12):3339-47. DOI: 10.1172/JCI26674
Source: PubMed

ABSTRACT Our understanding of thrombopoiesis--the formation of blood platelets--has improved greatly in the last decade, with the cloning and characterization of thrombopoietin, the primary regulator of this process. Thrombopoietin affects nearly all aspects of platelet production, from self-renewal and expansion of HSCs, through stimulation of the proliferation of megakaryocyte progenitor cells, to support of the maturation of these cells into platelet-producing cells. The molecular and cellular mechanisms through which thrombopoietin affects platelet production provide new insights into the interplay between intrinsic and extrinsic influences on hematopoiesis and highlight new opportunities to translate basic biology into clinical advances.

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    • "Signaling molecules bind to the phosphorylated tyrosine residues, and are phosphorylated by the kinase. Phosphorylated signaling molecules dissociate from the receptor, resulting in signal transduction to intracellular second messengers (Ihle, 1995; Kaushansky, 2005). The amino acid sequence surrounding the tyrosine residue determines whether a signaling molecule can bind to the tyrosine residue (Songyang et al., 1993). "
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    ABSTRACT: The technique to expand hematopoietic stem cells (HSCs) ex vivo is eagerly anticipated to secure an enough amount of HSCs for clinical applications. Previously we developed a scFv-thrombopoietin receptor (c-Mpl) chimera, named S-Mpl, which can transduce a proliferation signal in HSCs in response to a cognate antigen. However, a remaining concern of the S-Mpl chimera may be the magnitude of the cellular expansion level driven by this molecule, which was significantly less than that mediated by endogenous wild-type c-Mpl. In this study, we engineered a tyrosine motif located in the intracellular domain of S-Mpl based on a top-down approach in order to change the signaling properties of the chimera. The truncated mutant (trunc.) and an amino-acid substitution mutant (Q to L) of S-Mpl were constructed to investigate the ability of these mutants to expand HSCs. The result showed that the truncated and Q to L mutants gave higher and considerably lower number of the cells than unmodified S-Mpl, respectively. The proliferation level through the truncated mutant was even higher than that of non-transduced HSCs with the stimulation of a native cytokine, thrombopoietin. Moreover, we analyzed the signaling properties of the S-Mpl mutants in detail using a pro-B cell line Ba/F3. The data indicated that the STAT3 and STAT5 activation levels through the truncated mutant increased, whereas activation of the Q to L mutant was inhibited by a negative regulator of intracellular signaling, SHP-1. This is the first demonstration that a non-natural artificial mutant of a cytokine receptor is effective for ex vivo expansion of hematopoietic cells compared with a native cytokine receptor.
    Journal of Biotechnology 09/2013; 168(4). DOI:10.1016/j.jbiotec.2013.09.012 · 2.88 Impact Factor
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    • "Under stress conditions, platelet production (thrombopoiesis) increases more than tenfold, with the spleen contracting and more activated platelets released from the natural depot (Fig. 1). During the inflammatory response, platelet count further increases due to the abundant production of thrombopoietin [3]. Platelets as cytoplasmic fragments of the megakaryocyte lack nuclei, and their protein profile predominantly represents that of the progenitors. "
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    ABSTRACT: Platelets are intimately involved in hemostasis, inflammation, innate and adaptive immunity, tissue regeneration and other physiological and pathological processes. Their granular structure is programmed to release a wide range of bioactive substances in response to agonists. Upon activation, platelet membranes display thrombotic and inflammatory agents, which may take an active part in the pathophysiology of autoimmune and autoinflammatory disorders. The aim of this review is to analyze current evidence of platelet (dys)function in inflammatory rheumatic diseases and overview platelet-targeting mechanisms of antirheumatic drug therapies. A comprehensive search through Medline/PubMed, SciVerse/Scopus and Web of Science was performed for English-language original research papers, using the keywords related to platelets in autoimmune and autoinflammatory rheumatic disorders. Additionally, the Cochrane Collaboration database was searched for the literature on the effects of antirheumatic drugs on platelet function. A variety of platelet markers have been tested in systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, spondyloarthropathies, vasculitides, and some autoinflammatory disorders. It has been shown that platelets circulate in an activated state in most of these disorders and tend to form complexes with other inflammatory and immune cells. Thrombotic and inflammatory agents, released from platelets, may trigger disease-specific complications (e.g., extraarticular features, fibrosis in systemic sclerosis) and propagate endothelial dysfunction. Whether platelet activation is a primary or secondary feature in rheumatic disorders remains to be elucidated. Some widely used antirheumatic drugs may suppress thrombopoiesis and platelet activity, however the clinical implications of this effect have yet to be examined in specifically designed prospective studies. Large retrospective cohort studies supported the use of low-dose aspirin for suppressing platelet function and preventing cerebrovascular events in giant-cell arteritis. However, emerging data suggest that the releasate of activated platelets applied topically to the inflamed cartilage in arthritis or skin ulcers in scleroderma may suppress the inflammation and facilitate tissue repair. Taken together, current evidence necessitates a balanced approach to platelet-activating and suppressing drug therapies in inflammatory rheumatic diseases.
    Current pharmaceutical design 04/2013; 20(4). DOI:10.2174/138161282004140213143843 · 3.29 Impact Factor
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    • "MK and platelets, which are their progeny, are highly specialized cells that participate in hemostatic and inflammatory functions. Since each platelet lives only about 10 days, the platelet supply is continually renewed by production of new platelets from the maturation of MK [10]. "
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    ABSTRACT: Background: Thrombocytopenia (platelet counts less than 150,000/μl) is commonly encountered in various hematological disorders including myelodysplastic syndromes as well as various non-myelodysplastic hematological conditions. Aim: The present study was undertaken to calculate the prevalence of various conditions associated with thrombocytopenia and to record the megakaryocytic alterations in various cases of thrombocytopenia. Apart from this by means of statistical analysis it was tried to analyze whether a significant difference existed in megakaryocytic alteration noted in myelodysplastic versus non- myelodysplastic conditions. Materials and Methods: A prospective series of 60 bone marrow aspirations along with concomitant bone marrow biopsies was conducted in a tertiary care centre catering to both urban as well as rural population in north India. Statistical Analysis: The distribution of morphological changes in cases of non myelodysplastic conditions and myelodysplastic were compared using Chi-Square test. A p-value less than 0.05 was considered significant. Results: The commonest cause of thrombocytopenia for which bone marrow examination was sought was dimorphic anaemia (18 cases, 30%), followed by myelodysplastic syndrome (06 cases, 10%) which was followed equally by acute lymphocytic leukemia and blast crisis of chronic myeloid leukemia (CML). Of all the non-MDS conditions apart from dimorphic anaemia, idiopathic thrombocytopenic purpura and chronic myeloid leukemia (blast crisis); megakaryocytic dysplastic forms were not noted in any other condition. In cases of myelodysplasia; dysplastic forms, bare megakaryocytic nuclei, hypogranular forms and micromegakaryocytes were seen. Comparison between frequencies of normal, high and low number of nuclear lobes among MDS (n=9) and non MDS (n=68) conditions were found to be statistically significant. Conclusion: Further studies on the evaluation of megakaryocytic alteration and their contribution to thrombocytopenia can provide growing knowledge to the pathogenesis of numerous hematopoietic disorders that may identify broader clinical applications of the newer strategies to regulate platelet count and functioning.
    03/2013; 7(3):473-9. DOI:10.7860/JCDR/2013/5085.2801
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