The canonical Wnt pathway shapes niches supportive of hematopoietic stem/progenitor cells
The canonical Wnt pathway shapes niches supportive of hematopoietic stem/progenitor cells
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DOI：
10.1182/blood-2011-07-369199
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发表时间：
2012-02-16
期刊：
影响因子：
20.3
通讯作者：
Kincade, Paul W.
中科院分区：
文献类型：
--
作者：
Ichii, Michiko;Frank, Mark Barton;Kincade, Paul W.
关于调节造血细胞的存活、自我更新和分化的BM组分，已经积累了相当多的信息。在本研究中，我们研究了Wnt信号传导，并评估了其对人类和小鼠造血的影响。将造血干/祖细胞（HSPC）置于Wnt 3a转导的0 P9基质细胞上。阻断了B细胞、自然杀伤细胞和浆细胞样树突细胞的增殖和产生。此外，一些HSPC特征保持或重新获得沿着不同的谱系生成潜力。这些反应不是由Wnt 3a对HSPC的直接作用引起的，而是还需要OP 9细胞的改变。微阵列、PCR和流式细胞术实验显示，OP 9细胞获得成骨细胞特性，同时下调与间充质干细胞相关的一些特征，包括血管生成素1、c-Kit配体和VCAM-1的表达。相反，核心蛋白聚糖、腱生蛋白和纤调蛋白的产生显著增加。我们发现，这些细胞外基质组分中的至少一种，核心蛋白聚糖，是造血的调节剂：在将该蛋白聚糖加入OP 9共培养物后，核心蛋白聚糖引起的变化与Wnt 3a引起的变化相似。此外，骨髓和脾脏中的造血干细胞数量在核心蛋白聚糖敲除小鼠中升高。这些发现定义了一种机制，通过这种机制，经典Wnt信号可以塑造支持造血的小生境。（Blood.2012;119（7）：1683-1692）
Considerable information has accumulated about components of BM that regulate the survival, self-renewal, and differentiation of hematopoietic cells. In the present study, we investigated Wnt signaling and assessed its influence on human and murine hematopoiesis. Hematopoietic stem/progenitor cells (HSPCs) were placed on Wnt3a-transduced OP9 stromal cells. The proliferation and production of B cells, natural killer cells, and plasmacytoid dendritic cells were blocked. In addition, some HSPC characteristics were maintained or re-acquired along with different lineage generation potentials. These responses did not result from direct effects of Wnt3a on HSPCs, but also required alterations in the OP9 cells. Microarray, PCR, and flow cytometric experiments revealed that OP9 cells acquired osteoblastic characteristics while down-regulating some features associated with mesenchymal stem cells, including the expression of angiopoietin 1, the c-Kit ligand, and VCAM-1. In contrast, the production of decorin, tenascins, and fibromodulin markedly increased. We found that at least 1 of these extracellular matrix components, decorin, is a regulator of hematopoiesis: upon addition of this proteoglycan to OP9 co-cultures, decorin caused changes similar to those caused by Wnt3a. Furthermore, hematopoietic stem cell numbers in the BM and spleen were elevated in decorin-knockout mice. These findings define one mechanism through which canonical Wnt signaling could shape niches supportive of hematopoiesis. (Blood.2012;119(7):1683-1692)