Kaushansky, K. The molecular mechanisms that control thrombopoiesis. J Clin Invest 115: 3339-3347

Department of Medicine, Division of Hematology/Oncology, University of California, San Diego, California 92103-3931, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 01/2006; 115(12):3339-47. DOI: 10.1172/JCI26674
Source: PubMed


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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    • "Mtb and its components activate macrophages and lymphocytes, which then secrete cytokines (TNF-α, IL-6, IL-8, and IL-12) enabling the development of a cellular immune response [3,4]. Of these cytokines, TNF-α and IL-6 in particular affect maturation of thrombopoietic cells and secretion of platelets into the circulation [5]. The CRP level, ESR, and presence of reactive thrombocytosis can also reportedly be used to determine the disease activity, and these values are correlated with the disease severity [6-8]. "
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    ABSTRACT: Mean Platelet Volume (MPV) reflects the size of platelets. It has been shown to be inversely correlated with inflammation in some chronic inflammatory diseases. This prospective study aimed at showing the usability of MPV as an inflammation marker in patients with active pulmonary tuberculosis (PTB) by comparing them to healthy controls. Additionally, its relationship with other inflammatory markers such as C-reactive protein (CRP) and Erythrocyte Sedimentation Rate (ESR) as well as with radiological extent of disease was examined. The study included 82 patients with active PTB and 95 healthy subjects (the control group). A whole blood count was done; CRP and ESR levels were compared; and in the PTB group, the relationship of radiological extent of disease with MPV and other inflammation markers was investigated. MPV was 7.74+/-1.33 /muL in the PTB group and 8.2+/-1.13 /muL in the healthy group (p=0.005). The blood platelet count, and the CRP and ESR values were significantly higher in the active PTB group than in the control group (p<0.0001). While radiologic disease extent and MPV had no correlation (p=0.80), the CRP (r=0.26, p=0.003) and ESR levels (r=0.39, p=0.003) were significantly correlated with radiologic disease extent. MPV was found lower in PTB patients than in healthy controls. MPV does not reflect the severity of the disease. Using MPV as an inflammation marker in PTB and assessing it as a negative acute phase reactant do not seem very reliable.
    Multidisciplinary respiratory medicine 02/2014; 9(1):11. DOI:10.1186/2049-6958-9-11 · 0.15 Impact Factor
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    • "Thrombopoietin (TPO), through its receptor cMpl, is one of the main regulator of platelet count. TPO critically influences megakaryocyte (Mk) proliferation and differentiation through a complex signal transduction pathway.2 "
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    ABSTRACT: The relationship between thrombopoietin (TPO) and its receptor cMpl in thrombocytopenic conditions has not been entirely clarified. To elucidate this interplay may expand the spectrum of indications of TPO mimetics. In this study we have explored the relationship between TPO and cMpl in platelets and megakaryocytes of 43 patients with thrombocytopenia due to idiopathic thrombocytopenic purpura (ITP), bone marrow hypoplasia, myelodysplastic syndromes (MDS), and familial thrombocytopenia. Data were compared to cMpl and TPO in patients with a normal platelet count and in patients with thrombocytosis due to essential thrombocythemia (ET). All but familial patients showed higher TPO compared to controls. All thrombocytopenic states were invariably associated with increased expression of platelet cMPL compared to healthy controls. ET patients showed normal TPO and a trend toward a reduced cMpl expression. Immunofluorescence of bone marrow sections from patients with ITP and MDS failed to show a peculiar pattern compared to controls. Multiple mechanisms regulate TPO and cMpl in thrombocytopenic conditions.
    Hematology Reports 01/2014; 6(1):4996. DOI:10.4081/hr.2014.4996
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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 · 2.87 Impact Factor
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