Canonical Wnt pathway signaling suppresses VCAM-1 expression by marrow stromal and hematopoietic cells.
Canonical Wnt pathway signaling suppresses VCAM-1 expression by marrow stromal and hematopoietic cells.
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DOI：
10.1016/j.exphem.2008.08.008
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发表时间：
2009-01
影响因子：
2.6
通讯作者：
Kincade, Paul W.
中科院分区：
文献类型：
--
作者：
Malhotra, Sachin;Kincade, Paul W.
Wnt家族可能有助于骨髓造血干细胞（HSC）的维持，但有关机制仍存在许多问题。血管细胞粘附分子-1（VCAM-1）在骨髓的细胞室中表达，可能有助于HSC的生态位，但其组成性表达的机制在很大程度上是未知的。我们现在探索Wnt信号传导对骨髓基质细胞和造血细胞表达细胞粘附分子（CAM）的影响。采用重组Wnt配体、逆转录病毒Wnt转导以及与Wnt分泌细胞共培养的方法分析Wnt对基质细胞和造血细胞粘附分子表达的影响。还进行了体内实验以评估Wnt 3a诱导的VCAM-1缺陷型造血细胞植入骨髓的能力。我们现在报告说，β-连环蛋白依赖性经典Wnt信号通路负调节两种类型骨髓细胞上的VCAM-1表达。Wnt通路抑制剂Axin（细胞内）或Dkk 1（细胞外）阻断了可扩散Wnt 3a对VCAM-1的调节。有趣的是，脂多糖（LPS）恢复了相当程度的VCAM-1表达，表明Wnt和TLR 4信号通路之间的功能性串扰。通过暴露于Wnt 3a降低HSC富集的Lin-Sca-1+ c-KitHi Thy 1.1Lo细胞上的VCAM-1并不阻止它们的成功移植。我们的研究结果表明，细胞组成和居住在HSC龛可以响应Wnt配体和熄灭VCAM-1。这种反应对于造血细胞的输出可能是重要的。鉴于已知VCAM-1对炎症的贡献，这可能代表了治疗干预的新途径。
The Wnt family may contribute to hematopoietic stem cell (HSC) maintenance in bone marrow, but many questions remain concerning mechanisms. Vascular cell adhesion molecule-1 (VCAM-1) is expressed in cellular compartments of the bone marrow and might contribute to the HSC niche, but mechanisms concerning its constitutive expression are largely unknown. We now explore the influence of Wnt signaling on cellular adhesion molecule (CAM) expression by bone marrow stromal and hematopoietic cells. Recombinant Wnt ligands, retroviral Wnt transductions and co-cultures with Wnt secreting cells were used to analyze the effect of Wnt on adhesion molecule expression by stromal and hematopoietic cells. In vivo experiments were also done to assess the ability of Wnt3a induced, VCAM-1 deficient hematopoietic cells to engraft bone marrow. We now report that the beta-catenin dependent canonical Wnt signaling pathway negatively regulates VCAM-1 expression on two types of bone marrow cells. Wnt pathway inhibitors, Axin (intracellular) or Dkk1 (extracellular) blocked the regulation of VCAM-1 by diffusible Wnt3a. Interestingly, lipopolysaccharide (LPS) restored a substantial degree of VCAM-1 expression, suggesting functional cross-talk between Wnt and TLR4 signaling pathways. Decreasing VCAM-1 on HSC enriched Lin- Sca-1+ c-KitHi Thy1.1Lo cells by exposure to Wnt3a did not prevent their successful transplantation. Our results suggest that cells comprising and residing in the HSC niche can respond to Wnt ligands and extinguish VCAM-1. This response may be important for export of hematopoietic cells. Given the known contribution of VCAM-1 to inflammation, this may represent a new avenue for therapeutic intervention.
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