The Hippo signaling pathway effector YAP promotes salivary gland regeneration after injury

Salivary glands are damaged by radiotherapy for head and neck cancers, which often culminates in radiation-induced hyposalivation and xerostomia that may be permanent. Here, we identified a central role for YAP in the regenerative response of the salivary gland. Activation of the Hippo signaling pat...

Full description

Saved in:
Bibliographic Details
Published in:Science signaling 2021-12, Vol.14 (712), p.eabk0599-eabk0599
Main Authors: Rocchi, Cecilia, Cinat, Davide, Serrano Martinez, Paola, Bruin, Anne L Jellema-de, Baanstra, Mirjam, Brouwer, Uilke, Del Angel Zuivre, Cinthya, Schepers, Hein, van Os, Ronald, Barazzuol, Lara, Coppes, Robert P
Format: Article
Language:English
Subjects:
Accumulation
Acinar cells
Adaptor Proteins, Signal Transducing - metabolism
Cancer
Cell proliferation
Epithelium
Exocrine glands
Head
Head & neck cancer
Hippo Signaling Pathway
Homeostasis
Injuries
Irradiation
Kinases
Localization
Nuclear transport
Organoids
Phosphorylation
Protein Serine-Threonine Kinases - genetics
Radiation damage
Radiation effects
Radiation therapy
Regeneration
Saliva
Salivary gland
Salivary glands
Salivary Glands - metabolism
Signal Transduction
Signaling
Transcription
Translocation
Xerostomia
YAP-Signaling Proteins
Yes-associated protein
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Salivary glands are damaged by radiotherapy for head and neck cancers, which often culminates in radiation-induced hyposalivation and xerostomia that may be permanent. Here, we identified a central role for YAP in the regenerative response of the salivary gland. Activation of the Hippo signaling pathway inhibits the phosphorylation of YAP, leading to its nuclear translocation and transcriptional activity. Using mice with salivary gland injury induced by surgical ligation and salivary gland–derived organoids, we found that YAP nuclear localization in the salivary gland epithelium changed dynamically between homeostasis and regeneration. Whereas local injury had no effect on nuclear YAP localization in saliva-producing acinar cells, it triggered nuclear accumulation of YAP in saliva-transporting ductal cells. Injury also stimulated the proliferation of ductal cells, which were mainly quiescent under homeostatic conditions and in nonregenerating areas distal to the injury site, thus enabling salivary gland regeneration. Overexpressing YAP or driving YAP nuclear translocation by inhibiting upstream Hippo pathway kinases increased the capacity of mouse and human salivary gland cells, including human cells that had been irradiated, to form lobed organoids in vitro. Our results identify a YAP-driven regeneration program in salivary gland ductal cells that could be used to promote salivary gland regeneration after irradiation-induced damage.
ISSN:1945-0877
1937-9145
DOI:10.1126/scisignal.abk0599