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Thrombopoietin does not induce lineage-restricted commitment of Mpl-R
expressing pluripotent progenitors but permits their complete erythroid and
megakaryocytic differentiation
F Goncalves, C Lacout, JL Villeval, F Wendling, W Vainchenker and D Dumenil
Institut Gustave Roussy, INSERM, U362, Villejuif, France.
In this study, we examined the in vitro and in vivo effects of forced
expression of Mpl-R (the thrombopoietin receptor) on the progeny of murine
hematopoietic stem cells. Bone marrow cells from 5-FU-treated mice were
transduced with retroviral vectors containing the human Mpl-R cDNA, or the
neomycine gene as a control. After 7 days cocultivation on virus-producer
cells, GpE86-Mpl-R or Gp86-Neo, the types of hematopoietic progenitor cells
responding to thrombopoietin (TPO) were studied by clonogenic assays.
Mpl-R-infected cells gave rise to CFU- GEMM, BFU-E, CFU-MK, but not CFU-GM
while Neo-infected cells produced only megakaryocytic colonies. In
addition, when nonadherent cells from GpE86-Mpl-R cocultures were grown
with TPO as the only stimulus for 7 days, a marked expansion of CFU-GEMM,
BFU-E, and CFU-MK was observed, while no change in CFU-GM number was seen.
Erythroid and megakaryocytic maturation occurred in the presence of TPO
while a block in granulocytic differentiation was observed at the
myeloblast stage. The direct effects of TPO on Mpl-R-transduced progenitor
cells were demonstrated by single cell cloning experiments. To analyze the
effects of the constitutive expression of Mpl-R on the determination of
multipotent progenitors (CFU-S) and long-term repopulating stem cells,
Mpl-R- or Neo-infected cells were injected into lethally irradiated
recipient mice. No difference was seen in (1) the number of committed
progenitor cells contained in individual CFU-S12 whether colonies arose
from noninfected or Mpl-R-infected CFU-S; (2) the mean numbers of
progenitor cells per leg or spleen of mice reconstituted with Mpl-R- or
Neo-infected cells, 1 or 7 months after the graft; and (3) the blood
parameters of the two groups of animals, with the exception of a 50%
reduction in circulating platelet counts after 7 months in mice repopulated
with Mpl-R-infected bone marrow cells. These results indicate that
retrovirus-mediated expression of Mpl-R in murine stem cells does not
modify their ability to reconstitute all myeloid lineages of
differentiation and does not result in a preferential commitment toward the
megakaryocytic lineage.
Volume 89,
Issue 10,
pp. 3544-3553,
05/15/1997
Copyright © 1997 by The American Society of Hematology
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