Autocrine-paracrine VEGF loops potentiate the maturation of megakaryocytic precursors through Flt1 receptor.
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 O(2) 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.
Casella
Ida
I
Department of Hematology-Oncology, Istituto Superiore di Sanità, Rome, Italy.
Feccia
Tiziana
T
Chelucci
Cristiana
C
Samoggia
Paola
P
Castelli
Germana
G
Guerriero
Raffaella
R
Parolini
Isabella
I
Petrucci
Eleonora
E
Pelosi
Elvira
E
Morsilli
Ornella
O
Gabbianelli
Marco
M
Testa
Ugo
U
Peschle
Cesare
C
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002462:Cell Membrane / Q000737:chemistry; D002478:Cells, Cultured; D004247:DNA / Q000032:analysis; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D015672:Erythroid Precursor Cells / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D008222:Lymphokines / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D008533:Megakaryocytes / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D009000:Monocytes / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D010100:Oxygen / Q000008:administration & dosage; D011123:Polyploidy; D012333:RNA, Messenger / Q000032:analysis; D013926:Thrombopoietin / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D042442:Vascular Endothelial Growth Factors
D000911:Antibodies, Monoclonal; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004247:DNA; D013926:Thrombopoietin; D040281:Vascular Endothelial Growth Factor Receptor-1; D010100:Oxygen