Regulation of hematopoietic stem cells by their mature progeny.
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/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.
Molecular Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
Carolyn A
CA
de Graaf
Maria
M
Kauppi
Tracey
T
Baldwin
Craig D
CD
Hyland
Donald
D
Metcalf
Tracy A
TA
Willson
Marina R
MR
Carpinelli
Gordon K
GK
Smyth
Warren S
WS
Alexander
Douglas J
DJ
Hilton
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D008533:Megakaryocytes / Q000166:cytology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics / Q000378:metabolism; D053628:Receptors, Thrombopoietin / Q000378:metabolism; D013926:Thrombopoietin / Q000097:blood
D020598:Proto-Oncogene Proteins c-myb; D053628:Receptors, Thrombopoietin; D013926:Thrombopoietin; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse