[en] To assess the variation of thrombopoietin (TPO) responsiveness associated with megakaryocyte (MK) progenitor amplification, TPO dose-response curves were obtained for normal human, single-cell plated CD34(+)CD41(+) cells. The number of MKs per well was determined in situ and expressed as number of doublings (NbD). Dose-response curves of the mean frequency of clones of each size versus log TPO concentration showed highly significant differences in the TPO concentration needed for half-maximum generation of clones of different sizes (TPO50): 1.89 +/- 0.51 pg/mL for 1 MK clones; 7.75 +/- 0.81 pg/mL for 2 to 3 MK clones; 38.5 +/- 5.04 pg/mL for 4 to 7 MK clones, and 91.8 +/- 16.0 pg/mL for 8 to 15 MK clones. These results were consistent with a prediction of the generation-age model, because the number of previous doublings in vivo was inversely correlated with the number of residual doublings in vitro. TPO responsiveness decreased in vitro by a factor of 3.5 per doubling, reflecting the recruitment of progressively more ancestral progenitors. In support of this hypothesis, the more mature CD34(+)CD41(+)CD42(+) cell fraction had a lower TPO50 (P <.001), underwent fewer NbD (P <.001), and expressed a 2.8-fold greater median Mpl receptor density (P <.001) than the CD34(+)CD41(+)CD42(-) fraction. Progenitors that have completed their proliferative program have maximum factor responsiveness and are preferentially induced to terminal differentiation. (C) 2004 by The American Society of Hematology.
Disciplines :
Hematology
Author, co-author :
Paulus, Jean-Michel ; Université de Liège - ULiège -Belgium > Laboratory of Hematology, CHU du Sart Tilman, Liège
Debili, Najet; Institut National de la Santé et de la Recherche Médicale - (INSERM) U362 >
Larbret, Fréféric; Institut National de la Santé et de la Recherche Médicale - (INSERM) U362) > Institut Gustave Roussy, Villejuif, France
Levin, Jack; Univerity of California School of Medicine, San Francisco, USA > Department of Laboratory Medicine.
Vainchenker, William; Institut National de la Santé et de la Recherche Médicale - (INSERM) U362 > Institut Gustave Roussy, Villjuif, France
Language :
English
Title :
Thrombopoietin responsiveness reflects the number of doublings undergone by megakaryocyte progenitors
Publication date :
15 October 2004
Journal title :
Blood
ISSN :
0006-4971
eISSN :
1528-0020
Publisher :
American Society of Hematology, Washington, United States - District of Columbia
Volume :
104
Issue :
8
Pages :
2291-2298
Peer reviewed :
Peer Reviewed verified by ORBi
Name of the research project :
Thrombocytopoiesis;
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE] INSERM - Institut National de la Santé et de la Recherche Médicale [FR]
Commentary :
Progenitors that have completed their proliferative program have maximum factor responsiveness and are preferentially induced to terminal differentiation.
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