Minimal contribution of marrow-derived endothelial precursors to tumor vasculature
Minimal contribution of marrow-derived endothelial precursors to tumor vasculature
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DOI：
10.4049/jimmunol.175.5.2890
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发表时间：
2005-09-01
影响因子：
4.4
通讯作者：
Karsan, A
中科院分区：
文献类型：
--
作者：
Larrivée, B;Niessen, K;Karsan, A
在胚胎发育过程中，血管和造血细胞起源于一种常见的前体--血管母细胞。最近的证据表明，成人骨髓细胞中存在内皮前体，但这些前体是否在肿瘤新生血管中起作用尚不清楚。在这份报告中，我们证明了小鼠骨髓含有内皮祖细胞，它来自具有自我更新能力的细胞，并可以整合到肿瘤微血管中，尽管频率非常低。转基因双报告策略使我们能够明确证明肿瘤骨髓来源的内皮细胞是由骨髓前体细胞的转分化产生的，而不是通过细胞融合产生的。单细胞移植表明，一种共同的前体对造血系和内皮系都有贡献，从而证明了成体血管母细胞的存在。此外，我们证明，肿瘤细胞分泌的血管内皮生长因子-A的增加，以及骨髓细胞中血管内皮生长因子受体-2的激活，不会改变骨髓来源的内皮祖细胞的动员和整合到肿瘤血管中。最后，在人脐血细胞中，我们发现内皮前体仅占单个核细胞的1/10(7)，但在CD133(+)细胞群中高度浓缩。通过排除细胞融合，我们清楚地证明了成体血管母细胞的存在，但骨髓干细胞向内皮细胞分化是极其罕见的事件。此外，我们还发现，血管内皮生长因子-A对造血细胞的刺激不会显著改变这一过程。
During embryogenesis, vascular and hemopoietic cells originate from a common precursor, the hemangioblast. Recent evidence suggests the existence of endothelial precursors in adult bone marrow cells, but it is unclear whether those precursors have a role in tumor neovascularization. In this report, we demonstrate that murine bone marrow contains endothelial progenitors, which arise from a cell with self-renewing capacity, and can integrate into tumor microvasculature, albeit at a very low frequency. A transgenic double-reporter strategy allowed us to demonstrate definitively that tumor bone marrow-derived endothelial cells arise by transdifferentiation of marrow progenitors rather than by cell fusion. Single cell transplants showed that a common precursor contributes to both the hemopoietic and endothelial lineages, thus demonstrating the presence of an adult hemangioblast. Furthermore, we demonstrate that increased vascular endothelial growth factor (VEGF)-A secretion by tumor cells, as well as activation of VEGF receptor-2 in bone marrow cells does not alter the mobilization and incorporation of marrow-derived endothelial progenitors into tumor vasculature. Finally, in human umbilical cord blood cells, we show that endothelial precursors make up only similar to 1 in 10(7) mononuclear cells but are highly enriched in the CD133(+) cell population. By ruling out cell fusion, we clearly demonstrate the existence of an adult hemangioblast, but the differentiation of marrow stem cells toward the endothelial lineage is an extremely rare event. Furthermore, we show that VEGF-A stimulation of hemopoietic cells does not significantly alter this process.