Hedgehog actively maintains adult lung quiescence and regulates repair and regeneration.
Hedgehog actively maintains adult lung quiescence and regulates repair and regeneration.
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DOI：
10.1038/nature14984
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发表时间：
2015-10-22
期刊：
影响因子：
64.8
通讯作者：
Morrisey EE
中科院分区：
文献类型：
--
作者：
Peng T;Frank DB;Kadzik RS;Morley MP;Rathi KS;Wang T;Zhou S;Cheng L;Lu MM;Morrisey EE
出生后的组织静止被认为是一种默认状态，在没有增殖刺激，如损伤。先前的研究已经证明，某些胚胎发育程序在成年器官中被异常地重新激活，以驱动修复和再生，但还不清楚器官（如肺）中的静止是如何维持的，肺显示出非常低的细胞更新水平。我们现在证明，静止在成人肺是一个积极维持的状态，并调节刺猬信号。出生后肺内稳态上皮特异性音刺猬缺失导致邻近肺间充质增生性扩张。Hedgehog信号最初在上皮损伤的急性期下调，因为间充质作为响应增殖，但在损伤消退期间恢复到基线，因为恢复静止。在急性上皮损伤过程中hedgehog的激活减弱了肺间充质的增殖扩张，而hedgehog信号转导的失活阻止了损伤消退过程中静止的恢复。最后，我们表明，刺猬还调节上皮细胞的静止和再生，通过间充质反馈机制损伤的反应。这些结果表明，上皮间充质相互作用协调刺猬积极维持出生后的组织稳态，和刺猬在损伤过程中的失调导致异常修复和再生的肺。
Postnatal tissue quiescence is thought to be a default state in the absence of a proliferative stimulus such as injury. Previous studies have demonstrated that certain embryonic development programs are reactivated aberrantly in adult organs to drive repair and regeneration, it is not well understood how quiescence is maintained in organs such as the lung which displays a remarkably low level of cellular turnover. We now demonstrate that quiescence in the adult lung is an actively maintained state and is regulated by hedgehog signaling. Epithelial-specific deletion of sonic hedgehog during postnatal homeostasis in the lung results in a proliferative expansion of the adjacent lung mesenchyme. Hedgehog signaling is initially down-regulated during the acute phase of epithelial injury as the mesenchyme proliferates in response, but returns to baseline during injury resolution as quiescence is restored. Activation of hedgehog during acute epithelial injury attenuates the proliferative expansion of the lung mesenchyme, whereas inactivation of hedgehog signaling prevents the restoration of quiescence during injury resolution. Finally, we show that hedgehog also regulates epithelial quiescence and regeneration in response to injury via a mesenchymal feedback mechanism. These results demonstrate that epithelial-mesenchymal interactions coordinated by hedgehog actively maintains postnatal tissue homeostasis, and deregulation of hedgehog during injury leads to aberrant repair and regeneration in the lung.