Autocrine-paracrine VEGF loops potentiate the maturation of megakaryocytic precursors through Flt1 receptor
Autocrine-paracrine VEGF loops potentiate the maturation of megakaryocytic precursors through Flt1 receptor
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DOI：
10.1182/blood-2002-07-2184
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发表时间：
2003-02-15
期刊：
影响因子：
20.3
通讯作者：
Peschle, C
中科院分区：
文献类型：
--
作者：
Casella, I;Feccia, T;Peschle, C
血管内皮生长因子（VEGF）受体（VEGFR 1/Flt 1和VEGFR 2/KDR/Flk 1）在造血中的表达/功能正在接受审查。我们研究了Fitt和激酶结构域受体（KDR）在造血前体细胞上的表达，如在通过红细胞（E）、巨核细胞（Mk）、粒细胞（G）或单核细胞（Mo）谱系诱导成单系分化/成熟的CD 34（+）造血祖细胞（HPC）的液体培养中所评估的。在0.5%至1.5%的CD 34（+）细胞上表达的KDR在诱导分化时迅速下调。类似地，Flt 1在HPC中以非常低的水平存在，并且在E和G谱系中被下调;然而，Flt 1在Mo和Mk系列的前体中被诱导;即，其水平在Mo成熟过程中逐渐增加，并且在Mk谱系的初始-中间培养阶段达到峰值。功能实验表明，Mk和E，而不是G和Mo，前体释放大量的VEGF在培养基中，特别是在低O-2水平。VEGF释放对Mk成熟的功能作用是L，由2个系列的观察结果表明。(1)阻止前体膜上VEGF-Flt 1相互作用的分子（例如，可溶性Flt 1受体）显著抑制Mk多倍化。(2)加入外源性VEGF或胎盘生长因子（PlGF）显著增强Mk成熟。相反，VEGF不改变Mo分化/成熟。总之，我们的研究结果表明，在造血微环境中，自分泌VEGF环有助于通过Flt 1最佳Mk成熟。一个旁分泌环路涉及VEGF释放的E前体也可能运作。类似地，最近的研究表明，涉及VEGF和Flt 1/Flk 1受体的自分泌环介导造血干细胞的存活和分化。(C)2003年，美国血液学会。
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 Fitt and kinase domain receptor (KDR) on hematopoietic precursors, as evaluated in liquid culture of CD34(+) hematopoietic progenitor cells (HPCs) induced to unilineage differentiatiori/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; le, 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 L 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 (PIGF) 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. (C) 2003 by The American Society of Hematology.