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Expression of growth factor receptors in unilineage differentiation culture
of purified hematopoietic progenitors
U Testa, C Fossati, P Samoggia, R Masciulli, G Mariani, HJ Hassan, NM Sposi, R Guerriero, V Rosato, M Gabbianelli, E Pelosi, M Valtieri and C Peschle
Department of Hematology-Oncology Istituto Superiore di Sanita, University
La Sapienza, Rome, Italy.
We have evaluated the expression of growth factor receptors (GFRs) on early
hematopoietic progenitor cells (HPCs) purified from human adult peripheral
blood and induced in liquid suspension culture to unilineage
differentiation/maturation through the erythroid (E), granulocytic (G),
megakaryocytic (Mk), or monocytic (Mo) lineage. The receptors for basic
fibroblast GF (bFGF), erythropoietin (Epo), thrombopoietin (Tpo), and
macrophage colony-stimulating factor (MCSF) have been only assayed at mRNA
level; the majority of GFRs have been evaluated by both mRNA and protein
analyses: the expression patterns were consistent at both levels. In
quiescent HPCs the receptors for early-acting [flt3 ligand (FL), c-kit
ligand (KL), bFGF, interleukin-6 (IL-6)] and multilineage [IL-3,
granulocyte-macrophage CSF (GM-CSF)] HGFs are expressed at significant
levels but with different patterns, eg, kit and flt3 are detected on a
majority and minority of HPCs, respectively, whereas IL- 3Rs and GM-CSFRs
are present on almost all HPCs. In the four differentiation pathways,
expression of early-acting receptors shows a progressive decrease, more
rapidly for bFGFR-1 and flt3 than for c-kit; furthermore, c-kit is more
slowly downmodulated in the E and Mk than the G and Mo lineages. As a
partial exception, IL-6Rs are still detected through the early or late
stages of maturation in the Mk and Mo lineages, respectively. IL-3R
expression is progressively and rapidly downmodulated in both E and Mk
pathways, whereas it moderately decreases in the Mo lineage and is
sustained in the G series. The expression of GM-CSFR is gradually
downmodulated in all differentiation pathways, ie, the receptor density
markedly decreases but late erythroblasts are still partially GM-CSFR+ and
terminal G, Mk and Mo cells are essentially GM-CSFR+. Expression of
receptors for late-acting cytokines is lineage-specific. Thus, EpoR,
G-CSFR, TpoR, and M-CSFR exhibit a gradual induction followed by a
sustained expression in the E, G, MK, and Mo lineages, respectively. In the
other differentiation pathways the expression of these receptors is either
absent or initially low and there-after suppressed. These observations are
compatible with the following multi-step model. (1) The early-acting GFRs
are expressed on quiescent HPCs with different patterns, whereas the
multilineage GFRs are present on > or = 90% to 95% HPCs. (2)
Multilineage GFs, potentiated by early-acting HGFs, trigger HPCs into
cycling. HPC proliferation/differentiation is followed by declining
expression of the early-acting GFRs and in part of multilineage GFRs (see
above). (3) Multilineage GFs trigger the expression of the unilineage GFRs
(see Testa U, et al: Blood 81:1442, 1993). Interaction of each unilineage
GF with its receptor leads to sustained expression of the receptor
(possibly via transcription factors activating the receptor promoter) and
thus mediates differentiation/maturation through the pertinent lineage.
Volume 88,
Issue 9,
pp. 3391-3406,
11/01/1996
Copyright © 1996 by The American Society of Hematology
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