R-spondin substitutes for neuronal input for taste cell regeneration in adult mice
R-spondin substitutes for neuronal input for taste cell regeneration in adult mice
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DOI：
10.1073/pnas.2001833118
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发表时间：
2021-01-12
影响因子：
11.1
通讯作者：
Jiang, Peihua
中科院分区：
文献类型：
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作者：
Lin, Xiaoli;Lu, Chanyi;Jiang, Peihua
味蕾细胞在一生中不断再生。味蕾的维持依赖于成年味觉干细胞产生的新细胞不断替换衰老的味觉细胞。一个多世纪前，研究表明，味蕾在其支配神经被切断后退化，并且直到远处的味觉神经节神经元重新支配后才恢复。因此，神经元输入，可能通过神经元供应的因素，需要分化的味觉细胞的产生和味蕾的维持。然而，这种神经元提供的生态位因子的身份仍然不清楚。在这里，通过挖掘已发表的膝状体神经节神经元的RNA测序数据集，并通过原位杂交，我们证明，R-spondin-2，配体LGR 5及其同系物LGR 4/6和干细胞表达的E3连接酶Rnf 43/Znrf 3，在结节岩和膝状体神经节神经元中表达。使用舌咽神经横断模型，我们表明，通过腺病毒全身递送R-spondin可以促进分化的味觉细胞的产生，尽管去神经。因此，外源性R-spondin可以替代神经元输入用于味蕾细胞补充和味蕾维持。使用味觉类器官培养物，我们表明，R-spondin是产生分化的味觉细胞所必需的，并且在培养基中不存在R-spondin的情况下，味蕾细胞不会离体产生。因此，我们建议，R-spondin-2可能是长期寻找的神经元因子，作用于味觉干细胞，以维持味觉组织的稳态。
Taste bud cells regenerate throughout life. Taste bud maintenance depends on continuous replacement of senescent taste cells with new ones generated by adult taste stem cells. More than a century ago it was shown that taste buds degenerate after their innervating nerves are transected and that they are not restored until after reinnervation by distant gustatory ganglion neurons. Thus, neuronal input, likely via neuron-supplied factors, is required for generation of differentiated taste cells and taste bud maintenance. However, the identity of such a neuron-supplied niche factor(s) remains unclear. Here, by mining a published RNA-sequencing dataset of geniculate ganglion neurons and by in situ hybridization, we demonstrate that R-spondin-2, the ligand of Lgr5 and its homologs Lgr4/6 and stem-cell-expressed E3 ligases Rnf43/Znrf3, is expressed in nodose-petrosal and geniculate ganglion neurons. Using the glossopharyngeal nerve transection model, we show that systemic delivery of R-spondin via adenovirus can promote generation of differentiated taste cells despite denervation. Thus, exogenous R-spondin can substitute for neuronal input for taste bud cell replenishment and taste bud maintenance. Using taste organoid cultures, we show that R-spondin is required for generation of differentiated taste cells and that, in the absence of R-spondin in culture medium, taste bud cells are not generated ex vivo. Thus, we propose that R-spondin-2 may be the long-sought neuronal factor that acts on taste stem cells for maintaining taste tissue homeostasis.