Contrasting responses of lymphoid progenitors to canonical and noncanonical Wnt signals.
Contrasting responses of lymphoid progenitors to canonical and noncanonical Wnt signals.
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DOI：
10.4049/jimmunol.181.6.3955
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发表时间：
2008-09-15
期刊：
影响因子：
--
通讯作者：
Kincade PW
中科院分区：
文献类型：
--
作者：
Malhotra S;Baba Y;Garrett KP;Staal FJ;Gerstein R;Kincade PW
分泌性糖蛋白的Wnt家族与发育的许多方面有关，但其对血细胞形成的贡献存在争议。我们在来自骨石化小鼠的基质细胞中过表达Wnt 3a、Wnt 5a和Dkk 1，并将它们用于与高度富集的干细胞和祖细胞的共培养实验。目的是了解特定阶段的B淋巴细胞生成是否以及如何对这些Wnt家族配体产生应答。我们发现经典Wnt信号通过Wnt 3a抑制B和pDC，但不抑制cDC的发育。Wnt 5a可以对抗经典信号传导或通过不同的途径起作用，增加B淋巴细胞生成。对两种Wnt配体的反应性随着培养时间和发育阶段而降低。也就是说，只有造血干细胞（HSC）和非常原始的祖细胞受到影响。虽然Wnt 3a促进HSC标记物的保留，但细胞产率和染料稀释实验表明它不是生长刺激物。其他结果表明，谱系不稳定性是由经典Wnt信号传导引起的。当暴露于产生Wnt 3a的基质细胞时，类造血祖细胞迅速下调RAG-1和一些获得性干细胞染色特征以及骨髓和红细胞潜能。我们的结论是，至少有两个Wnt配体可以差异调节B淋巴细胞生成的早期事件，影响不同分化谱系的进入和进展。
The Wnt family of secreted glycoproteins has been implicated in many aspects of development, but its contribution to blood cell formation is controversial. We over-expressed Wnt3a, Wnt5a and Dkk1 in stromal cells from osteopetrotic mice and used them in co-culture experiments with highly enriched stem and progenitor cells. The objective was to learn if and how particular stages of B lymphopoiesis are responsive to these Wnt family ligands. We found that canonical Wnt signaling, through Wnt3a, inhibited B and pDC but not cDC development. Wnt5a, which can oppose canonical signaling or act through a different pathway, increased B lymphopoiesis. Responsiveness to both Wnt ligands diminished with time in culture and stage of development. That is, only hematopoietic stem cells (HSCs) and very primitive progenitors were affected. While Wnt3a promoted retention of HSC markers, cell yields and dye dilution experiments indicated it was not a growth stimulus. Other results suggest that lineage instability results from canonical Wnt signaling. Lymphoid progenitors rapidly down-regulated RAG-1 and some acquired stem cell staining characteristics as well as myeloid and erythroid potential when exposed to Wnt3a producing stromal cells. We conclude that at least two Wnt ligands can differentially regulate early events in B lymphopoiesis, affecting entry and progression in distinct differentiation lineages.
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