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Long-term functional regeneration of radiation-damaged salivary glands through delivery of a neurogenic hydrogel

Jianlong Li, Sonia Sudiwala, Lionel Berthoin, Alison J. May, Seayar Mohabbat, Hanan Sinada, Eliza A. Gaylord, Noel Cruz Pacheco, View ORCID ProfileIsabelle M.A. Lombaert, Oju Jeon, Eben Alsberg, Chelsea S. Bahney, View ORCID ProfileSarah M. Knox
doi: https://doi.org/10.1101/2022.05.19.491203
Jianlong Li
1University of California, San Francisco. Department of Cell & Tissue Biology, San Francisco, CA
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Sonia Sudiwala
1University of California, San Francisco. Department of Cell & Tissue Biology, San Francisco, CA
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Lionel Berthoin
1University of California, San Francisco. Department of Cell & Tissue Biology, San Francisco, CA
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Alison J. May
1University of California, San Francisco. Department of Cell & Tissue Biology, San Francisco, CA
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Seayar Mohabbat
1University of California, San Francisco. Department of Cell & Tissue Biology, San Francisco, CA
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Hanan Sinada
1University of California, San Francisco. Department of Cell & Tissue Biology, San Francisco, CA
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Eliza A. Gaylord
1University of California, San Francisco. Department of Cell & Tissue Biology, San Francisco, CA
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Noel Cruz Pacheco
1University of California, San Francisco. Department of Cell & Tissue Biology, San Francisco, CA
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Isabelle M.A. Lombaert
2University of Michigan. Biointerfaces Institute. Ann Arbor, MI
3University of Michigan. School of Dentistry. Department of Biologic and Materials Sciences. Ann Arbor, MI
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  • ORCID record for Isabelle M.A. Lombaert
Oju Jeon
4University of Illinois, Chicago. Department of Bioengineering and Orthopaedics, Chicago, IL
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Eben Alsberg
4University of Illinois, Chicago. Department of Bioengineering and Orthopaedics, Chicago, IL
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Chelsea S. Bahney
5University of California, San Francisco. Orthopaedic Trauma Institute, San Francisco, CA
6Steadman Philippon Research Institute. Center for Regenerative Sports Medicine, Vail, CO
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Sarah M. Knox
1University of California, San Francisco. Department of Cell & Tissue Biology, San Francisco, CA
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  • ORCID record for Sarah M. Knox
  • For correspondence: Sarah.Knox@UCSF.edu
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Abstract

Salivary gland acinar cells are severely depleted after radiotherapy for head and neck cancer, leading to loss of saliva and extensive oro-digestive complications. With no regenerative therapies available, organ dysfunction is irreversible. Here using the adult murine system, we demonstrate radiation-damaged salivary glands can be functionally regenerated via sustained delivery of the neurogenic muscarinic receptor agonist, cevimeline. We show that endogenous gland repair coincides with increased nerve activity and acinar cell division that is limited to the first week post-radiation, with extensive acinar cell degeneration, dysfunction and cholinergic denervation occurring thereafter. However, we discovered that mimicking cholinergic muscarinic input via sustained local delivery of a cevimeline-alginate hydrogel was sufficient to regenerate innervated acini and retain physiological saliva secretion at non-irradiated levels over the long-term (> 3 months). Thus, we reveal a novel regenerative approach for restoring epithelial organ structure and function that has significant implications for human patients.

Teaser Novel application of an injectable neurogenic-based hydrogel for restoring the structure and function of radiation-damaged tissue.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 19, 2022.
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Long-term functional regeneration of radiation-damaged salivary glands through delivery of a neurogenic hydrogel
Jianlong Li, Sonia Sudiwala, Lionel Berthoin, Alison J. May, Seayar Mohabbat, Hanan Sinada, Eliza A. Gaylord, Noel Cruz Pacheco, Isabelle M.A. Lombaert, Oju Jeon, Eben Alsberg, Chelsea S. Bahney, Sarah M. Knox
bioRxiv 2022.05.19.491203; doi: https://doi.org/10.1101/2022.05.19.491203
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Long-term functional regeneration of radiation-damaged salivary glands through delivery of a neurogenic hydrogel
Jianlong Li, Sonia Sudiwala, Lionel Berthoin, Alison J. May, Seayar Mohabbat, Hanan Sinada, Eliza A. Gaylord, Noel Cruz Pacheco, Isabelle M.A. Lombaert, Oju Jeon, Eben Alsberg, Chelsea S. Bahney, Sarah M. Knox
bioRxiv 2022.05.19.491203; doi: https://doi.org/10.1101/2022.05.19.491203

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