Neurotrophin signaling is a central mechanism of salivary dysfunction after irradiation that disrupts myoepithelial cells

Alejandro M Chibly; Vaishali N Patel; Marit H Aure; Mary C Pasquale; NIDCD/NIDCR Genomics and Computational Biology Core; Gemma E Martin; Mousa Ghannam; Julianne Andrade; Noah G Denegre; Colleen Simpson; David P Goldstein; Fei-Fei Liu; Isabelle M A Lombaert; Matthew P Hoffman

doi:10.1038/s41536-023-00290-7

Neurotrophin signaling is a central mechanism of salivary dysfunction after irradiation that disrupts myoepithelial cells

NPJ Regen Med. 2023 Mar 25;8(1):17. doi: 10.1038/s41536-023-00290-7.

Authors

Collaborators

NIDCD/NIDCR Genomics and Computational Biology Core:
Robert J Morell, Daniel Martin Izquierdo, Erich Boger

Affiliations

¹ Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA. martinez-chibly.agustin@gene.com.
² Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA.
³ Department of Otolaryngology-Head & Neck Surgery, Princess Margaret Cancer Center, Toronto, ON, M5G 2C4, Canada.
⁴ Department of Radiation Oncology, Princess Margaret Cancer Center, Toronto, ON, M5G 2M9, Canada.
⁵ Department of Biologic and Material Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, 48109, USA.
⁶ Biointerfaces Institute, University of Michigan, Ann Arbor, MI, 48109, USA.
⁷ Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA. mhoffman@nih.gov.

Abstract

The mechanisms that prevent regeneration of irradiated (IR) salivary glands remain elusive. Bulk RNAseq of IR versus non-IR human salivary glands showed that neurotrophin signaling is highly disrupted post-radiation. Neurotrophin receptors (NTRs) were significantly upregulated in myoepithelial cells (MECs) post-IR, and single cell RNAseq revealed that MECs pericytes, and duct cells are the main sources of neurotrophin ligands. Using two ex vivo models, we show that nerve growth factor (NGF) induces expression of MEC genes during development, and upregulation of NTRs in adult MECs is associated with stress-induced plasticity and morphological abnormalities in IR human glands. As MECs are epithelial progenitors after gland damage and are required for proper acinar cell contraction and secretion, we propose that MEC-specific upregulation of NTRs post-IR disrupts MEC differentiation and potentially impedes the ability of the gland to regenerate.