A novel nonpeptidyl human c-Mpl activator stimulates human megakaryopoiesis and thrombopoiesis

Nakamura, Takanori; Miyakawa, Yoshitaka; Miyamura, Atsushi; Yamane, Akiko; Suzuki, Hitomi; Ito, Mamoru; Ohnishi, Yasuyuki; Ishiwata, Norihisa; Ikeda, Yasuo; Tsuruzoe, Nobutomo

doi:10.1182/blood-2005-11-4433

Cited by 83 publications

(77 citation statements)

References 34 publications

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“…Oral administration of YM477 dose-dependently increased the number of human platelets produced by these mice, reaching an increase of about 3AE0-fold on day 14. (Nakamura et al, 2006). The efficacy and safety of these molecules in clinical settings has yet to be determined.…”

Section: Clinical Use Of Thrombopoietic Agentsmentioning

confidence: 99%

Megakaryocyte development and platelet production

2006

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SummaryMegakaryocytopoiesis involves the commitment of haematopoietic stem cells, and the proliferation, maturation and terminal differentiation of the megakaryocytic progenitors. Circulating levels of thrombopoietin (TPO), the primary growth-factor for the megakaryocyte (MK) lineage, induce concentration-dependent proliferation and maturation of MK progenitors by binding to the c-Mpl receptor and signalling induction. Decreased platelet turnover rates results in increased concentration of free TPO, enabling the compensatory response of marrow MKs to increased platelet production. C-Mpl activity is orchestrated by a complex cascade of signalling molecules that induces the action of specific transcription factors to drive MK proliferation and maturation. Mature MKs form proplatelet projections that are fragmented into circulating particles. Newly developed thrombopoietic agents operating via c-Mpl receptor may prove useful in supporting platelet production in thrombocytopenic state. Herein, we review the regulation of megakaryocytopoiesis and platelet production in normal and disease state, and the new approaches to thrombopoietic therapy.

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Section: Clinical Use Of Thrombopoietic Agentsmentioning

confidence: 99%

Megakaryocyte development and platelet production

2006

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“…These characteristics indicate that NOG mice constitute an excellent humanized mouse model in which engrafted cells and tissues function as they do in humans [8]. At present, various studies using humanized mouse models based on NOG mice have been carried out in various fields of human disease research [10,11,19], where they have proved to be very useful tools. The immunological deficiencies that underlie the high engraftment levels of NOG mice are derived from three immunodeficient mice.…”

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confidence: 99%

Immunodeficient NOD-scid IL-2R.GAMMA.null Mice Do Not Display T and B Cell Leakiness

et al. 2011

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[7]. These characteristics indicate that NOG mice constitute an excellent humanized mouse model in which engrafted cells and tissues function as they do in humans [8]. At present, various studies using humanized mouse models based on NOG mice have been carried out in various fields of human disease research [10,11,19], where they have proved to be very useful tools. The immunological deficiencies that underlie the high engraftment levels of NOG mice are derived from three immunodeficient mice. Reduced macrophage function and complement activity originate from a NOD inbred strain [17], T and B cell deficiencies from SCID mice with the scid mutation [1], and NK cell deficiency and multiple cytokine dysfunction from null KO mice [13]. Among these immunodeficiencies, the lack of functional T and B cells in mice with the scid mutation is a result of defective gene recombination events in T cell receptors (TCR) and immunoglobulins [16]. These mice -Note-

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“…This compound stimulates the proliferation or differentiation of human c-Mpl-expressing cells such as UT-7/TPO and human CD34 ϩ cells. 7) In immunodeficient nonobese diabetic/Shi-scid, IL-2Rg (null) mice receiving transplants of CB-derived CD34 ϩ cells, NIP-004 increased human megakaryoblasts, mature megakaryocytes, and circulating human platelets 6-fold, the latter being morphologically and functionally indistinguishable from normal human platelets. As shown in these reports, the developments regarding the novel molecules for thrombopoiesis such as non-peptidyl low molecular weight compounds are becoming active.…”

Section: Discussionmentioning

confidence: 99%

“…Although TPO-like activity has been discussed with regard to some low molecule peptide and non-peptide synthesis compounds, neither of the compounds under study has resulted in a clinical application as a platelet hematinic thus far. [5][6][7] On the other hand, although many investigations regarding the characteristics and development of liquid crystal compounds have been studied in order to obtain superior compounds, 8) little information has been reported to date regarding their biological potential. The structure of an amphiphilic liquid crystal compound has a common structure with the cell membrane in that each has both a hydrophilic and hydrophobic residue, thus suggesting an affinity to the cellular membrane.…”

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confidence: 99%

The Promoting Activity on Human Megakaryocytopoiesis and Thrombopoiesis by Liquid Crystal-Related Compounds

Terasawa

Fukushi

Monzen

et al. 2009

Biological & Pharmaceutical Bulletin

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The liquid crystal compounds have a common structure with the cell membrane, having both a hydrophilic and hydrophobic residue, thus suggesting an affinity to the cell membrane. However, little information regarding a biological effect by liquid crystal compounds has been reported. In order to view the biological potential of liquid crystal compounds, the present study evaluated the in vitro human hematopoietic promoting effects by 18 liquid crystal-related compounds. In particular, these compounds are evaluated regarding their potential for platelet production from mature megakaryocytes by the culturing of CD34 ؉ cells derived from normal human peripheral blood. Often, in the case of severe thrombocytopenia there is no choice but to perform a transfusion of platelet concentrates. Three of the tested compounds promoted megakacyocyte generation in the culture stimulated with thrombopoietin alone. In addition, two compounds led to a significant increase in CD42a؉ particles which seemed to be platelets. At the same time, interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF), that were used as a positive control for in vitro megakaryocytopoiesis and thrombopoiesis, resulted in a dramatic increase in the total number of cells; however, their promoting activity on in vitro hematopoiesis was almost at a similar level with the compounds. These results suggest that some liquid crystal-related compounds have a promoting effect on human thrombopoiesis, and that these compounds act with a different mechanism from either IL-3 or GM-CSF since the compounds specifically stimulated thrombopoiesis. The liquid crystal compounds may therefore be useful to develop a new functional medicine or a medical application.

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A novel nonpeptidyl human c-Mpl activator stimulates human megakaryopoiesis and thrombopoiesis

Cited by 83 publications

References 34 publications

Megakaryocyte development and platelet production

Megakaryocyte development and platelet production

Immunodeficient NOD-scid IL-2R.GAMMA.null Mice Do Not Display T and B Cell Leakiness

The Promoting Activity on Human Megakaryocytopoiesis and Thrombopoiesis by Liquid Crystal-Related Compounds

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