Cellular senescence contributes to radiation-induced hyposalivation by affecting the stem/progenitor cell niche

Abstract

Radiotherapy for head and neck cancer is associated with impairment of salivary gland function and consequent xerostomia, which has a devastating effect on the quality of life of the patients. The mechanism of radiation-induced salivary gland damage is not completely understood. Cellular senescence is a permanent state of cell cycle arrest accompanied by a secretory phenotype which contributes to inflammation and tissue deterioration. Genotoxic stresses, including radiation-induced DNA damage, are known to induce a senescence response. Here, we show that radiation induces cellular senescence preferentially in the salivary gland stem/progenitor cell niche of mouse models and patients. Similarly, salivary gland-derived organoids show increased expression of senescence markers and pro-inflammatory senescence-associated secretory phenotype (SASP) factors after radiation exposure. Clearance of senescent cells by selective removal of p16Ink4a-positive cells by the drug ganciclovir or the senolytic drug ABT263 lead to increased stem cell self-renewal capacity as measured by organoid formation efficiency. Additionally, pharmacological treatment with ABT263 in mice irradiated to the salivary glands mitigates tissue degeneration, thus preserving salivation. Our data suggest that senescence in the salivary gland stem/progenitor cell niche contributes to radiation-induced hyposalivation. Pharmacological targeting of senescent cells may represent a therapeutic strategy to prevent radiotherapy-induced xerostomia.

Radiation-Induced Salivary Gland Dysfunction: Mechanisms, Therapeutics and Future Directions

“…Senescence as a result of IR can similarly inhibit regenerative potential. In a recent study, C57BL/6 mice receiving 15 Gy X-ray IR were treated with the senolytic drug, ABT263, by oral gavage at 8 or 11 weeks post-IR [ 68 ]. ABT263, which inhibits BCL-2 and BCL-xL, selectively eliminates senescent cells.…”

“…ABT263, which inhibits BCL-2 and BCL-xL, selectively eliminates senescent cells. Pilocarpine-stimulated saliva secretion demonstrated a restoration of salivary gland function in irradiated mice receiving ABT263, compared to those receiving IR and vehicle [ 68 ]. Additionally, these mice had reduced expression of senescence markers and an increase in aquaporin 5-expressing acinar cells in the SMGs [ 68 ].…”

“…Pilocarpine-stimulated saliva secretion demonstrated a restoration of salivary gland function in irradiated mice receiving ABT263, compared to those receiving IR and vehicle [ 68 ]. Additionally, these mice had reduced expression of senescence markers and an increase in aquaporin 5-expressing acinar cells in the SMGs [ 68 ]. The authors conclude that clearance of senescent cells promotes self-renewal of the stem/progenitor niche and restoration of salivary gland function [ 68 ].…”

Current and Future Perspectives of the Use of Organoids in Radiobiology

“…Studies using cultured media from irradiated cells has long been shown to induce paracrine bystander effects in non-irradiated cells [ 134 ] and such techniques may be insightful into the effects of secreted SASP proteins on untreated cells or organoids. Indeed, our group recently demonstrated that cultured media from irradiation-induced senescent organoids inhibits organoid forming efficiency in freshly passaged salivary gland-derived organoids [ 135 ]; however, these models still lack a true interaction between treated and non-treated organoids and the potential paracrine effects of other tissues in their vicinity in vivo.…”

Apoptosis-resistance of senescent cells is an intrinsic barrier for senolysis induced by cardiac glycosides

“…), and chemotherapy-induced (activated in cancer cells in response to chemotherapeutic drugs) (Campisi, 1996;Serrano et al, 1997;Toussaint, et al, 2000;Roninson et al, 2001). There Recently, using high-throughput drug screening two independent research groups identified cardiac glycosides, particularly ouabain, digoxin and bufalin, as a broad-spectrum senolytics (Guerrero et Nevertheless, there are only few experimental data regarding this issue (Grezella et al, 2018;Peng et al, 2020;Sharma et al, 2020;.…”