Salivary glands regenerate after radiation injury through SOX2-mediated secretory cell replacement.

Elaine Emmerson,Aaron D Tward,Aaron J Mattingly,Lionel Berthoin,Jolie L Chang,William R Ryan,Sarah M Knox,Sara Nathan,Noel Cruz-Pacheco,Alison J May

doi:10.15252/emmm.201708051

Elaine Emmerson, Aaron D Tward + Show 8 more

Open Access

https://doi.org/10.15252/emmm.201708051

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Abstract

Salivary gland acinar cells are routinely destroyed during radiation treatment for head and neck cancer that results in a lifetime of hyposalivation and co‐morbidities. A potential regenerative strategy for replacing injured tissue is the reactivation of endogenous stem cells by targeted therapeutics. However, the identity of these cells, whether they are capable of regenerating the tissue, and the mechanisms by which they are regulated are unknown. Using in vivo and ex vivo models, in combination with genetic lineage tracing and human tissue, we discover a SOX2+ stem cell population essential to acinar cell maintenance that is capable of replenishing acini after radiation. Furthermore, we show that acinar cell replacement is nerve dependent and that addition of a muscarinic mimetic is sufficient to drive regeneration. Moreover, we show that SOX2 is diminished in irradiated human salivary gland, along with parasympathetic nerves, suggesting that tissue degeneration is due to loss of progenitors and their regulators. Thus, we establish a new paradigm that salivary glands can regenerate after genotoxic shock and do so through a SOX2 nerve‐dependent mechanism.

Highlights

Therapeutic radiation continues to be a life-saving treatment for cancer patients and is utilized for a spectrum of malignancies including those of the head and neck
We found SOX2 to be expressed by a subset of acinar cells in all three of the major adult human salivary glands [Fig 1A, submandibular gland (SMG), sublingual gland (SLG), parotid gland (PG)]
SOX2 protein was restricted to the adult murine SLG where it was expressed by undifferentiated aquaporin (AQP)5-positive, mucin (MUC)19-negative acinar cells (21 Æ 4% of all AQP5+ acinar cells; Fig 1C and D)

Summary

Introduction

Therapeutic radiation continues to be a life-saving treatment for cancer patients and is utilized for a spectrum of malignancies including those of the head and neck. The vast majority of patients suffering head and neck cancer will receive radiotherapy in addition to chemotherapy and surgery (~60,000 new patients per year in US; Siegel et al, 2015). This combination treatment is highly efficacious in eliminating tumors, a severe side effect is damage and/or destruction of healthy tissue lying in the field of radiation. Such organs include the salivary glands, which exhibit tissue dysfunction even after low doses of radiation (Grundmann et al, 2009). There has been success with intensity modulated radiation to spare one of the three major salivary glands (parotid), the proximity of the glands to the tumor sites often prevents application of this technique, leaving 80% of head and neck cancer patients with dry mouth syndrome (Lee & Le, 2008)

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