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Thrombopoietin stimulates megakaryocytopoiesis, myelopoiesis, and expansion
of CD34+ progenitor cells from single CD34+Thy-1+Lin- primitive progenitor
cells
JC Young, E Bruno, KM Luens, S Wu, M Backer and LJ Murray
SyStemix Inc, Palo Alto, CA 94304, USA.
Thrombopoietin (TPO) or MpI ligand is known to stimulate megakaryocyte (MK)
proliferation and differentiation. To identify the earliest human
hematopoietic cells on which TPO acts, we cultured single CD34+Thy- 1+Lin-
adult bone marrow cells in the presence of TPO alone, with TPO and
interleukin-3 (IL-3), or with TPO and c-kit ligand (KL) in the presence of
a murine stromal cell line (Sys1). Two distinct growth morphologies were
observed: expansion of up to 200 blast cells with subsequent
differentiation to large refractile CD41b+ MKs within 3 weeks or expansion
to 200-10,000 blast cells, up to 25% of which expressed CD34. The latter
blast cell expansions occurred over a 3- to 6-week period without obvious
MK differentiation. Morphological staining, analysis of surface marker
expression, and colony formation analysis revealed that these populations
consisted predominantly of cells committed to the myelomonocytic lineage.
The addition of IL-3 to TPO-containing cultures increased the extent of
proliferation of single cells, whereas addition of KL increased the
percentage of CD34+ cells among the expanding cell populations. Production
of multiple colony- forming unit-MK from single CD34+Thy-1+Lin- cells in
the presence of TPO was also demonstrated. In limiting dilution assays of
CD34+Lin- cells, TPO was found to increase the size and frequency of
cobblestone areas at 4 weeks in stromal cultures in the presence of
leukemia inhibitory factor and IL-6. In stroma-free cultures, TPO activated
a quiescent CD34+Lin-Rhodamine 123lo subset of primitive hematopoietic
progenitor cells into cycle, without loss of CD34 expression. These data
demonstrate that TPO acts directly on and supports division of cells more
primitive than those committed to the MK lineage.
Volume 88,
Issue 5,
pp. 1619-1631,
09/01/1996
Copyright © 1996 by The American Society of Hematology
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