Chemokine signaling is required for homeostatic and injury‐induced neurogenesis in the olfactory epithelium
Chemokine signaling is required for homeostatic and injury‐induced neurogenesis in the olfactory epithelium
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DOI：
10.1002/stem.3338
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发表时间：
2021-01
期刊：
影响因子：
5.2
通讯作者：
Katja Senf;J. Karius;R. Stumm;E. Neuhaus
中科院分区：
文献类型：
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作者：
Katja Senf;J. Karius;R. Stumm;E. Neuhaus
嗅觉上皮（OE）具有独特的终生神经再生能力，并在哺乳动物的整个生命周期中经历组成性神经发生。两类干细胞，即经常分裂的球状基底细胞（GBC）和静止的水平基底细胞（HBC），在整个生命周期中很容易取代嗅觉神经元。尽管干细胞的谱系定型和神经元分化已经通过转录因子表达进行了描述，但对于分化和自我更新之间的外部因素平衡知之甚少。我们在此表明，CXC 基序趋化因子受体 4 (CXCR4) 的表达可以区分两种类型的干细胞。广泛的共定位分析揭示了 CXCR4 在增殖的 GBC 及其神经元后代中的唯一表达。此外，只有神经元谱系细胞来自 OE 中的 CXCR4-CreER-tdTomato 报告小鼠。此外，当与带有 floxed CXCR4 等位基因的小鼠交配时，对 HBC（Nestin+ 和 Cytokeratin14+）具有特异性的 Cre-tdTomato 小鼠并没有降低 CXCR4 的表达，并且没有显示出神经元细胞的标记。 CXCR4 及其配体 CXCL12 在损伤诱导的再生过程中诱导 GBC 增殖后显着上调。 CXCL12 的体内过度表达确实下调了 CXCR4 水平，从而导致 GBC 维持和神经元分化减少。我们通过证明 CXCL12 过表达小鼠的表型与 CXCR4 敲除小鼠的表型高度相似，证明了这些效应是由 CXCR4 下调而不是过度激活引起的。我们的结果表明 GBC 中的功能性 CXCR4 信号传导可调节细胞周期退出和神经分化。我们认为 CXCR4/CXCL12 信号传导是嗅觉神经发生的重要调节因子，并为 OE 中神经发生的动态提供了新的见解。
The olfactory epithelium (OE) possesses unique lifelong neuroregenerative capacities and undergoes constitutive neurogenesis throughout mammalian lifespan. Two populations of stem cells, frequently dividing globose basal cells (GBCs) and quiescent horizontal basal cells (HBCs), readily replace olfactory neurons throughout lifetime. Although lineage commitment and neuronal differentiation of stem cells has already been described in terms of transcription factor expression, little is known about external factors balancing between differentiation and self‐renewal. We show here that expression of the CXC‐motif chemokine receptor 4 (CXCR4) distinguishes both types of stem cells. Extensive colocalization analysis revealed exclusive expression of CXCR4 in proliferating GBCs and their neuronal progenies. Moreover, only neuronal lineage cells were derived from CXCR4‐CreER‐tdTomato reporter mice in the OE. Furthermore, Cre‐tdTomato mice specific for HBCs (Nestin+ and Cytokeratin14+) did not reduce CXCR4 expression when bred to mice bearing floxed CXCR4 alleles, and did not show labeling of the neuronal cells. CXCR4 and its ligand CXCL12 were markedly upregulated upon induction of GBC proliferation during injury‐induced regeneration. in vivo overexpression of CXCL12 did downregulate CXCR4 levels, which results in reduced GBC maintenance and neuronal differentiation. We proved that these effects were caused by CXCR4 downregulation rather than over‐activation by showing that the phenotypes of CXCL12‐overexpressing mice were highly similar to the phenotypes of CXCR4 knockout mice. Our results demonstrate functional CXCR4 signaling in GBCs regulates cell cycle exit and neural differentiation. We propose that CXCR4/CXCL12 signaling is an essential regulator of olfactory neurogenesis and provide new insights into the dynamics of neurogenesis in the OE.