Thrombopoietin signaling is required for in vivo expansion of IL-11--responsive hematopoietic progenitor cells in the steady state.
OBJECTIVE
mpl(-/-) mice have a profound defect in platelets and megakaryocytes and a defect in hematopoietic progenitor cells and stem cells. However, no specific subset of the progenitor/stem cell compartment has been shown to be particularly affected by this deficiency in mpl(-/-) mice. In this article, we identified a specific subset of bone marrow progenitor/stem cells that was altered in mpl(-/-) mice.


METHODS
In vitro and in vivo hematopoietic assays were utilized to examine the response to interleukin-11 in mice lacking the receptor for thrombopoietin (TPO) (mpl(-/-) mice).


RESULTS
The interleukin (IL)-11-responsive subset of progenitor cells was not detected in clonal cultures of bone marrow cells from mpl(-/-) mice. However, mpl(-/-) mice responded to IL-11 in vivo as evidenced by a rise in platelet count and an increase in spleen weight. Experiments were performed to address this paradox: administration of 5-fluorouracil with consequent "expansion" of early hematopoietic cells resulted in the appearance of IL-11-responsive cells in mpl(-/-) mice when assayed in in vitro cultures.


CONCLUSIONS
Thus, although mpl(-/-) mice have the capacity to produce IL-11-responsive progenitor cells, under steady state conditions their expansion is dependent on TPO. This is the first evidence that a specific subset of bone marrow progenitor/stem cells is altered in mpl(-/-) mice.
Scott
C L
CL
The Walter and Eliza Hall Institute of Medical Research, P.O. Royal Melbourne Hospital, Victoria, Australia. scottc@wehi.edu.au
Robb
L
L
Nandurkar
H H
HH
Mansfield
R
R
Alexander
W S
WS
Begley
C G
CG
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D017370:Interleukin-11 / Q000494:pharmacology*; D007377:Interleukin-3 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009363:Neoplasm Proteins; D010976:Platelet Count; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000502:physiology; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D019089:Stem Cell Factor / Q000494:pharmacology; D013926:Thrombopoietin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D017370:Interleukin-11; D007377:Interleukin-3; D015850:Interleukin-6; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D019089:Stem Cell Factor; C082218:MPL protein, human; D013926:Thrombopoietin; D005472:Fluorouracil