Competitive balance of intrabulge BMP/Wnt signaling reveals a robust gene network ruling stem cell homeostasis and cyclic activation
Competitive balance of intrabulge BMP/Wnt signaling reveals a robust gene network ruling stem cell homeostasis and cyclic activation
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DOI：
10.1073/pnas.1121312110
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发表时间：
2013-01-22
影响因子：
11.1
通讯作者：
Kobielak, Krzysztof
中科院分区：
文献类型：
--
作者：
Kandyba, Eve;Leung, Yvonne;Kobielak, Krzysztof
毛囊有利于干细胞行为的研究，因为干细胞在渐进的激活阶段，有序的毛囊结构，能够循环再生。为了研究支配毛发隆突干细胞稳态的基因网络，我们开发了一种角蛋白15驱动的遗传模型来直接干扰干细胞中的分子信号传导。我们可视化这些修饰的干细胞的行为，评估它们的毛发再生能力并分析它们的分子表达。骨形态发生蛋白（BMP）灭活的干细胞表现出类似于毛胚的分子特征，但在体内仍具有多潜能性。这些细胞还表现出Wnt 7a、Wnt 7 b和Wnt 16配体以及Frizzled（Fzd）10受体的上调。我们证明了Wnt 7a启动子的直接转录调节。这些结果突出了BMP和Wnt信号传导之间的先前未知的干细胞内拮抗竞争，以平衡干细胞活性。基于依赖于BMP/Wnt活性比率的连续标度，BMP信号传导减少和Wnt信号传导增加使每个干细胞向毛胚命运倾斜，反之亦然。这项工作揭示了在干细胞-真皮乳头为基础的上皮-间充质相互作用层和毛囊-真皮内脂肪细胞为基础的组织相互作用层之下的一个调节干细胞稳态的多层次层。虽然分层都是基于BMP/Wnt信号传导，但多层控制确保所有信息都被考虑在内，并允许毛干细胞总结参与激活决定的总激活剂/抑制剂。
Hair follicles facilitate the study of stem cell behavior because stem cells in progressive activation stages, ordered within the follicle architecture, are capable of cyclic regeneration. To study the gene network governing the homeostasis of hair bulge stem cells, we developed a Keratin 15-driven genetic model to directly perturb molecular signaling in the stem cells. We visualize the behavior of these modified stem cells, evaluating their hair-regenerating ability and profile their molecular expression. Bone morphogenetic protein (BMP)-inactivated stem cells exhibit molecular profiles resembling those of hair germs, yet still possess multipotentiality in vivo. These cells also exhibit up-regulation of Wnt7a, Wnt7b, and Wnt16 ligands and Frizzled (Fzd) 10 receptor. We demonstrate direct transcriptional modulation of the Wnt7a promoter. These results highlight a previously unknown intra-stem cell antagonistic competition, between BMP and Wnt signaling, to balance stem cell activity. Reduced BMP signaling and increased Wnt signaling tilts each stem cell toward a hair germ fate and, vice versa, based on a continuous scale dependent on the ratio of BMP/Wnt activity. This work reveals one more hierarchical layer regulating stem cell homeostasis beneath the stem cell-dermal papilla-based epithelial-mesenchymal interaction layer and the hair follicle-intradermal adipocyte-based tissue interaction layer. Although hierarchical layers are all based on BMP/Wnt signaling, the multilayered control ensures that all information is taken into consideration and allows hair stem cells to sum up the total activators/inhibitors involved in making the decision of activation.