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

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.

Salivary gland stem cells: A review of development, regeneration and cancer

“…Kwak et al utilized an inducible Cre under the control of the Krt14 promotor to demonstrate that cells marked by KRT14 i.e., myoepithelial cells and basal cells located in the intercalated ducts, give rise to cells of the granular convoluted tubules but not intercalated ducts, myoepithelial cells or acinar cells (Kwak et al , 2016). We also recently showed through long term genetic lineage tracing of KIT+ cells that these cells, even after 6 months, contribute solely to the intercalated duct cells and not acinar cells of the homeostatic SG (Emmerson et al , 2018). In concordance with these results, Aure et al demonstrated that acini give rise exclusively to acini and not to the ductal system.…”

“…Although from this study it was postulated that acinar cell replacement is mediated by self-duplication, whether a bona fide progenitor contributes to the acinar lineage was not known. We recently reported the presence of an acinar progenitor population, marked by SOX2 (Arnold et al, 2011; Figure 3), that gives rise to differentiated MUC19+ acinar cells of the SLG during homeostasis and after injury (Emmerson et al , 2018). Furthermore, ablation of SOX2+ cells results in a striking loss of acinar cells and deletion of Sox2 impairs acinar cell replenishment after radiation-induced damage, suggesting that SOX2+ cells are the sole progenitors of the murine SLG.…”

“…Furthermore, ablation of SOX2+ cells results in a striking loss of acinar cells and deletion of Sox2 impairs acinar cell replenishment after radiation-induced damage, suggesting that SOX2+ cells are the sole progenitors of the murine SLG. A recent study using the single cell colony method suggested SOX2+ cells may also be progenitors for human SG (all three major SG have a subpopulation of acini that are SOX2+ (Emmerson et al, 2018)) as these colonies expressed SOX2 and engrafted into SCID mice (Lu et al , 2015). Similar to the developing SG, SOX2+ cells and SOX2-mediated acinar cell replacement are dependent on functional parasympathetic innervation, with administration of acetylcholine muscarinic mimetics being sufficient to drive acinar cell regeneration in mice and promote SOX2 expression and the acinar lineage in human SG (Emmerson et al , 2018).…”

“…A recent study using the single cell colony method suggested SOX2+ cells may also be progenitors for human SG (all three major SG have a subpopulation of acini that are SOX2+ (Emmerson et al, 2018)) as these colonies expressed SOX2 and engrafted into SCID mice (Lu et al , 2015). Similar to the developing SG, SOX2+ cells and SOX2-mediated acinar cell replacement are dependent on functional parasympathetic innervation, with administration of acetylcholine muscarinic mimetics being sufficient to drive acinar cell regeneration in mice and promote SOX2 expression and the acinar lineage in human SG (Emmerson et al , 2018). As parasympathetic nerves and SOX2+ cells are diminished in irradiated human SG (Emmerson et al , 2018), tissue degeneration may be due to a loss of progenitor cells and the cues that regulate them.…”

“…Similar to the developing SG, SOX2+ cells and SOX2-mediated acinar cell replacement are dependent on functional parasympathetic innervation, with administration of acetylcholine muscarinic mimetics being sufficient to drive acinar cell regeneration in mice and promote SOX2 expression and the acinar lineage in human SG (Emmerson et al , 2018). As parasympathetic nerves and SOX2+ cells are diminished in irradiated human SG (Emmerson et al , 2018), tissue degeneration may be due to a loss of progenitor cells and the cues that regulate them. However, many more studies are needed to determine if these are the sole progenitors or if other subsets of progenitors exist.…”