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Accelerated reconstitution of platelets and erythrocytes after syngeneic
transplantation of bone marrow cells derived from thrombopoietin pretreated
donor mice
WE Fibbe, DP Heemskerk, L Laterveer, JF Pruijt, D Foster, K Kaushansky and R Willemze
Department of Hematology, University Medical Center Leiden, The
Netherlands.
The recent cloning of the ligand of the c-Mpl hematopoietin receptor has
indicated a major role for this cytokine in the development of
megakaryocytes. In this study we have applied c-Mpl ligand (thrombopoietin
[TPO]) in the setting of syngeneic transplantation in an attempt to
accelerate the reconstitution of platelets. Donor mice were treated with 20
kilounits (kU)/d TPO intraperitoneally (ip) for 5 days. This resulted in a
2.5-fold increment in platelet counts from 1,119 x 10(9)/L to 2,582 x
10(9)/L (mean, n = 7). Total numbers of hematopoietic progenitor cells in
bone marrow (BM) and spleen, as assessed in a colony-forming
unit-granulocyte erythroid monocyte macrophage (CFU-GEMM) colony assay
(55.3 v 38.6 x 10(3) CFU/femur; 27.3 v 16.3 x 10(3) CFU/spleen, mean, n =
7) as well as total numbers of burst-forming unit-erythroid (BFU-E) (24.0 v
16.4 x 10(3)/femur; 10.2 v 1.9 x 10(3)/spleen, mean, n = 7), were
significantly higher in TPO- treated donors than in saline-treated
controls. Female Balb-C mice were lethally (8.5 Gy) irradiated and
transplanted with 10(5) BM cells. After transplantation, groups of mice
were treated with recombinant murine TPO at a dose of 20 to 30 kU/d ip or
subcutaneously (SC) for 5 to 14 days. Using this dose and schedule, TPO did
not stimulate the recovery of platelets in comparison with control animals
transplanted with equal cell numbers but given vehicle alone. In other
experiments, 10(5) BM cells were procured from TPO-treated donor mice and
transplanted into lethally irradiated recipient mice. In comparison with
animals transplanted with an equal number of BM cells derived from
saline-treated controls, recipients of TPO-treated BM cells had
significantly faster platelet recovery and higher platelet nadir counts (88
v 30 x 10(9)/L, mean, n = 20). Transplantation of TPO-treated BM cells also
resulted in an accelerated recovery of erythrocytes and increased
erythrocyte nadir counts (7.2 v 5.0 x 10(12)/L, mean, n = 20). At the day
of platelet nadir (day 12 after transplantation) these animals had higher
numbers of BFU-Es (770 v 422, mean, n = 5) in the marrow and also had
higher reticulocyte counts (44 / 1000 v 8 / 1000 mean, n = 5) in the blood.
Therefore, the accelerated recovery of erythrocytes may be a direct effect
of TPO on erythropoiesis.(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 86,
Issue 9,
pp. 3308-3313,
11/01/1995
Copyright © 1995 by The American Society of Hematology
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