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Regulation of hematopoietic stem cells by their mature progeny
Carolyn A. de Graafa,b, Maria Kauppic, Tracey Baldwina, Craig D. Hylandc, Donald Metcalfc,1, Tracy A. Willsona, Marina R. Carpinellia, Gordon K. Smythd,e, Warren S. Alexanderc,b,2, and Douglas J. Hiltona,b,1,2
+ Author Affiliations
aMolecular Medicine Division,
cCancer and Haematology Division, and
dBioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; and
Departments of bMedical Biology and
eMathematics and Statistics, University of Melbourne, Parkville, Victoria 3010, Australia
Contributed by Donald Metcalf, October 27, 2010 (sent for review August 23, 2010)
?2W.S.A. and D.J.H. contributed equally to this work.
Abstract
Thrombopoietin (TPO), acting through its receptor Mpl, has two major physiological roles: ensuring production of sufficient platelets via stimulation of megakaryocyte production and maintaining hematopoietic stem cell (HSC) quiescence. Mpl also controls circulating TPO concentration via receptor-mediated internalization and degradation. Here, we demonstrate that the megakaryocytosis and increased platelet mass in mice with mutations in the Myb or p300 genes causes reduced circulating TPO concentration and TPO starvation of the stem-cell compartment, which is exacerbated because these cells additionally exhibit impaired responsiveness to TPO. HSCs from MybPlt4/Plt4 mice show altered expression of TPO-responsive genes and, like HSCs from Tpo and Mpl mutant mice, exhibit increased cycling and a decline in the number of HSCs with age. These studies suggest that disorders of platelet number can have profound effects on the HSC compartment via effects on the feedback regulation of circulating TPO concentration.
