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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-07-2184.
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Blood, 15 February 2003, Vol. 101, No. 4, pp. 1316-1323
HEMATOPOIESIS
Autocrine-paracrine VEGF loops potentiate the maturation of
megakaryocytic precursors through Flt1 receptor
Ida Casella,
Tiziana Feccia,
Cristiana Chelucci,
Paola Samoggia,
Germana Castelli,
Raffaella Guerriero,
Isabella Parolini,
Eleonora Petrucci,
Elvira Pelosi,
Ornella Morsilli,
Marco Gabbianelli,
Ugo Testa, and
Cesare Peschle
From the Department of Hematology-Oncology,
Istituto Superiore di Sanità, Rome, Italy; Thomas
Jefferson University, Kimmel Cancer Center, Philadelphia, PA.
The expression/function of vascular endothelial growth factor
(VEGF) receptors (VEGFR1/Flt1 and VEGFR2/KDR/Flk1) in hematopoiesis is
under scrutiny. We have investigated the expression of Flt1 and kinase
domain receptor (KDR) on hematopoietic precursors, as evaluated
in liquid culture of CD34+ hematopoietic progenitor cells
(HPCs) induced to unilineage differentiation/maturation through the
erythroid (E), megakaryocytic (Mk), granulocytic (G), or monocytic (Mo)
lineage. KDR, expressed on 0.5% to 1.5% CD34+ cells, is
rapidly downmodulated on induction of differentiation. Similarly, Flt1
is present at very low levels in HPCs and is downmodulated in E and G
lineages; however, Flt1 is induced in the precursors of both Mo and Mk
series; ie, its level progressively increases during Mo maturation, and
it peaks at the initial-intermediate culture stages in the Mk lineage.
Functional experiments indicate that Mk and E, but not G and Mo,
precursors release significant amounts of VEGF in the culture medium,
particularly at low O2 levels. The functional role of VEGF
release on Mk maturation is indicated by 2 series of observations.
(1) Molecules preventing the VEGF-Flt1 interaction on the precursor
membrane (eg, soluble Flt1 receptors) significantly inhibit Mk
polyploidization. (2) Addition of exogenous VEGF or placenta growth
factor (PlGF) markedly potentiates Mk maturation. Conversely, VEGF does
not modify Mo differentiation/maturation. Altogether, our results
suggest that in the hematopoietic microenvironment an autocrine
VEGF loop contributes to optimal Mk maturation through Flt1. A
paracrine loop involving VEGF release by E precursors may also operate.
Similarly, recent studies indicate that an autocrine loop involving
VEGF and Flt1/Flk1 receptors mediates hematopoietic stem cell survival
and differentiation.
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