Regulation of hematopoietic stem cells by their mature progeny

Carolyn A de Graaf, Maria Kauppi, Tracey M Baldwin, Craig D Hyland, Donald Metcalf, Tracy A Willson, Marina Carpinelli, Gordon K Smyth, Warren Alexander, Douglas Hilton

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51 Citations (Scopus)


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 Myb Plt4/Plt4mice show altered expression of TPOresponsive 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.
Original languageEnglish
Pages (from-to)21689 - 21694
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number50
Publication statusPublished - 2010
Externally publishedYes

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