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Multi-level effects of flt3 ligand on human hematopoiesis: expansion of
putative stem cells and proliferation of granulomonocytic
progenitors/monocytic precursors
M Gabbianelli, E Pelosi, E Montesoro, M Valtieri, L Luchetti, P Samoggia, L Vitelli, T Barberi, U Testa and S Lyman
Department of Hematology-Oncology, Instituto Superiore di Sanita, Rome,
Italy.
We have evaluated the effects of the flt3 receptor ligand (FL) on
hematopoietic progenitors/stem cells (HPCs/HSCs) stringently purified from
adult peripheral blood and grown in different culture systems. In these
experiments HPCs/HSCs were treated with FL +/- kit ligand (KL) +/- monocyte
colony-stimulatory factor (M-CSF). In clonogenetic HPC culture supplemented
with interleukin-3 (IL-3)/granulomonocyte-CSF (GM- CSF)/erythropoietin
(Epo), FL potentiates colony-forming unit (CFU)-GM proliferation in terms
of colony number and size, but exerts little effect on burst-forming
units-erythroid (BFU-E) and CFU-granulocyte erythroid megakaryocyte
macrophage (CFU-GEMM) growth, whereas KL enhances the proliferation of all
HPC types; combined FL+KL +/- M-CSF treatment causes a striking shift of
CFU-GM colonies from granulocytic to monocytic differentiation. In liquid
suspension HPC culture, FL alone induces differentiation along the
monocytic and to a minor extent the basophilic lineages, whereas M-CSF
alone stimulates prevalent monocytic differentiation but little cell
proliferation: combined M- CSF+FL treatment causes both proliferation and
almost exclusive monocytic differentiation (97% monocytes in fetal calf
serum-rich (FCS+) culture conditions, mean value). At primitive HPC level,
FL potentiates the clonogenetic capacity of colony-forming units-blast
(CFU-B) and high proliferative potential colony-forming cells (HPP-CFC) in
primary and secondary culture; KL exerts a similar action, and additive
effects are induced by FL combined with KL. More important, addition of FL
alone causes a significant amplification of the number of long-term
culture-initiating cells (LTC-ICs), ie, putative repopulating HSCs, whereas
this effect is not induced by KL. The FL effects correlate with flt3 mRNA
expression in HPCs differentiating throught the erythroid or GM pathway in
liquid suspension culture: (1) flt3 mRNA is expressed in freshly purified,
resting HPCs; after growth factor stimulus the message (2) is abruptly
down-modulated in HPC erythroid differentiation, but (3) is sustainedly
expressed through HPC GM differentiation and abolished in GM precursor
maturation. This pattern contrasts with the gradual downmodulation of c-kit
through both erythroid and GM HPC differentiation. The results indicate
that FL exerts a stimulatory action on primitive HPCs, including a unique
expanding effect on putative stem cells, whereas its distal
proliferative/differentiative action is largely restricted to CFU-GM and
monocytic precursors. The latter effect is potentiated by KL and M- CSF,
thus suggesting that the structural similarities of FL, KL, M-CSF, and
their tyrosine kinase receptors may mediate positive interactions of these
growth factors son monocytic differentiation.
Volume 86,
Issue 5,
pp. 1661-1670,
09/01/1995
Copyright © 1995 by The American Society of Hematology
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