Neuroendocrine cells orchestrate regeneration through Desert hedgehog signaling

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Pub Date : 2025-06-09 DOI:10.1016/j.cell.2025.05.012

William Kong, Wan-Jin Lu, Megha Dubey, Rahul K. Suryawanshi, Sivakamasundari Vijayakumar, Youngtae Jeong, Saurabh Gombar, Maximilian Diehn, Kunyoo Shin, Melanie Ott, Yueh-hsiu Chien, Kavita Y. Sarin, Tushar J. Desai, Philip A. Beachy

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Abstract

Understanding the mechanisms underlying mammalian regeneration may enable development of novel regenerative therapies. We present a mechanism wherein Desert hedgehog (Dhh), secreted from epithelial neuroendocrine cells, elicits a regenerative/protective response from mesenchymal cells. In mammalian airway, this mesenchymal response strikingly amplifies the initial signal from rare neuroendocrine cells to activate the entire tissue for survival and regeneration upon injury from SO₂ gas inhalation or following influenza or SARS-CoV-2 infection. Similar epithelial-mesenchymal feedback (EMF) signaling directed by Dhh from neuroendocrine β cells likewise protects mouse pancreatic islets from streptozotocin (STZ) injury. A role for EMF signaling in human pancreatic islets is suggested by higher incidence of diabetes in patients treated with Hedgehog pathway inhibitors. Remarkably, EMF augmentation by small-molecule Hedgehog pathway agonism protects against STZ injury of pancreatic β cells and shields against airway injury from SO₂ and influenza infection, with potential protective/therapeutic utility in chemical or infectious airway injury and in diabetes.

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神经内分泌细胞通过沙漠刺猬信号调控再生

了解哺乳动物再生的机制可能有助于开发新的再生疗法。我们提出了一种机制，其中从上皮神经内分泌细胞分泌的沙漠刺猬（Dhh）引起间充质细胞的再生/保护反应。在哺乳动物气道中，这种间充质反应显著地放大了来自罕见神经内分泌细胞的初始信号，以激活整个组织，以便在吸入二氧化硫气体或感染流感或SARS-CoV-2后存活和再生。类似的由神经内分泌β细胞Dhh引导的上皮-间充质反馈（EMF）信号同样保护小鼠胰岛免受链脲佐菌素（STZ）损伤。使用Hedgehog通路抑制剂治疗的患者糖尿病发病率较高，这表明EMF信号在人胰岛中的作用。值得注意的是，通过小分子Hedgehog通路激动作用增强EMF可以保护胰腺β细胞免受STZ损伤，并保护SO2和流感感染引起的气道损伤，在化学或感染性气道损伤和糖尿病中具有潜在的保护/治疗作用。

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.