The evolving definition of salivary gland stem cells

Dysfunction of the salivary gland and irreversible hyposalivation are the main side effects of radiotherapy treatment for head and neck cancer leading to a drastic decrease of the quality of life of the patients. Approaches aimed at regenerating damaged salivary glands have been proposed as means to provide long-term restoration of tissue function in the affected patients. In studies to elucidate salivary gland regenerative mechanisms, more and more evidence suggests that salivary gland stem/progenitor cell behavior, like many other adult tissues, does not follow that of the hard-wired professional stem cells of the hematopoietic system. In this review, we provide evidence showing that several cell types within the salivary gland epithelium can serve as stem/progenitor-like cells. While these cell populations seem to function mostly as lineage-restricted progenitors during homeostasis, we indicate that upon damage specific plasticity mechanisms might be activated to take part in regeneration of the tissue. In light of these insights, we provide an overview of how recent developments in the adult stem cell research field are changing our thinking of the definition of salivary gland stem cells and their potential plasticity upon damage. These new perspectives may have important implications on the development of new therapeutic approaches to rescue radiation-induced hyposalivation

A Coalgebraic View of Infinite Trees and Iteration

AbstractThe algebra of infinite trees is, as proved by C. Elgot, completely iterative, i.e., all ideal recursive equations are uniquely solvable. This is proved here to be a general coalgebraic phenomenon: let H be an endofunctor such that for every object X a final coalgebra, TX, of H(_) + X exists. Then TX is an object-part of a monad which is completely iterative. Moreover, a similar contruction of a “completely iterative monoid” is possible in every monoidal category satisfying mild side conditions

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

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

Mitophagy induction improves salivary gland stem/progenitor cell function by reducing senescence after irradiation

BACKGROUND AND PURPOSE: Patients undergoing radiotherapy for head and neck cancer often experience a decline in their quality of life due to the co-irradiation of salivary glands. Radiation-induced cellular senescence is a key factor contributing to salivary gland dysfunction. Interestingly, mitochondrial dysfunction and cellular senescence have been reported to be strongly interconnected and thus implicated in several aging-related diseases. This study aims to investigate the role of mitochondrial dysfunction in senescence induction in salivary gland stem/progenitor cells after irradiation.MATERIALS AND METHODS: A dose of 7 Gy photons was used to irradiate mouse salivary gland organoids. Senescent markers and mitochondrial function were assessed using rt-qPCR, western blot analysis, SA-β-Gal staining and flow cytometry analysis. Mitochondrial dynamics-related proteins were detected by western blot analysis while Mdivi-1 and MFI8 were used to modulate the mitochondrial fission process. To induce mitophagy, organoids were treated with Urolithin A and PMI and subsequently stem/progenitor cell self-renewal capacity was assessed as organoid forming efficiency.RESULTS: Irradiation led to increased senescence and accumulation of dysfunctional mitochondria. This was accompanied by a strong downregulation of mitochondrial fission-related proteins and mitophagy-related genes. After irradiation, treatment with the mitophagy inducer Urolithin A attenuated the senescent phenotype and improved organoid growth and stem/progenitor cell self-renewal capacity.CONCLUSION: This study shows the important interplay between senescence and mitochondrial dysfunction after irradiation. Importantly, activation of mitophagy improved salivary gland stem/progenitor cell function thereby providing a novel therapeutic strategy to restore the regenerative capacity of salivary glands following irradiation.</p

Mitophagy induction improves salivary gland stem/progenitor cell function by reducing senescence after irradiation

BACKGROUND AND PURPOSE: Patients undergoing radiotherapy for head and neck cancer often experience a decline in their quality of life due to the co-irradiation of salivary glands. Radiation-induced cellular senescence is a key factor contributing to salivary gland dysfunction. Interestingly, mitochondrial dysfunction and cellular senescence have been reported to be strongly interconnected and thus implicated in several aging-related diseases. This study aims to investigate the role of mitochondrial dysfunction in senescence induction in salivary gland stem/progenitor cells after irradiation.MATERIALS AND METHODS: A dose of 7 Gy photons was used to irradiate mouse salivary gland organoids. Senescent markers and mitochondrial function were assessed using rt-qPCR, western blot analysis, SA-β-Gal staining and flow cytometry analysis. Mitochondrial dynamics-related proteins were detected by western blot analysis while Mdivi-1 and MFI8 were used to modulate the mitochondrial fission process. To induce mitophagy, organoids were treated with Urolithin A and PMI and subsequently stem/progenitor cell self-renewal capacity was assessed as organoid forming efficiency.RESULTS: Irradiation led to increased senescence and accumulation of dysfunctional mitochondria. This was accompanied by a strong downregulation of mitochondrial fission-related proteins and mitophagy-related genes. After irradiation, treatment with the mitophagy inducer Urolithin A attenuated the senescent phenotype and improved organoid growth and stem/progenitor cell self-renewal capacity.CONCLUSION: This study shows the important interplay between senescence and mitochondrial dysfunction after irradiation. Importantly, activation of mitophagy improved salivary gland stem/progenitor cell function thereby providing a novel therapeutic strategy to restore the regenerative capacity of salivary glands following irradiation.</p

Mitophagy induction improves salivary gland stem/progenitor cell function by reducing senescence after irradiation

BACKGROUND AND PURPOSE: Patients undergoing radiotherapy for head and neck cancer often experience a decline in their quality of life due to the co-irradiation of salivary glands. Radiation-induced cellular senescence is a key factor contributing to salivary gland dysfunction. Interestingly, mitochondrial dysfunction and cellular senescence have been reported to be strongly interconnected and thus implicated in several aging-related diseases. This study aims to investigate the role of mitochondrial dysfunction in senescence induction in salivary gland stem/progenitor cells after irradiation.MATERIALS AND METHODS: A dose of 7 Gy photons was used to irradiate mouse salivary gland organoids. Senescent markers and mitochondrial function were assessed using rt-qPCR, western blot analysis, SA-β-Gal staining and flow cytometry analysis. Mitochondrial dynamics-related proteins were detected by western blot analysis while Mdivi-1 and MFI8 were used to modulate the mitochondrial fission process. To induce mitophagy, organoids were treated with Urolithin A and PMI and subsequently stem/progenitor cell self-renewal capacity was assessed as organoid forming efficiency.RESULTS: Irradiation led to increased senescence and accumulation of dysfunctional mitochondria. This was accompanied by a strong downregulation of mitochondrial fission-related proteins and mitophagy-related genes. After irradiation, treatment with the mitophagy inducer Urolithin A attenuated the senescent phenotype and improved organoid growth and stem/progenitor cell self-renewal capacity.CONCLUSION: This study shows the important interplay between senescence and mitochondrial dysfunction after irradiation. Importantly, activation of mitophagy improved salivary gland stem/progenitor cell function thereby providing a novel therapeutic strategy to restore the regenerative capacity of salivary glands following irradiation.</p

Mitophagy induction improves salivary gland stem/progenitor cell function by reducing senescence after irradiation

BACKGROUND AND PURPOSE: Patients undergoing radiotherapy for head and neck cancer often experience a decline in their quality of life due to the co-irradiation of salivary glands. Radiation-induced cellular senescence is a key factor contributing to salivary gland dysfunction. Interestingly, mitochondrial dysfunction and cellular senescence have been reported to be strongly interconnected and thus implicated in several aging-related diseases. This study aims to investigate the role of mitochondrial dysfunction in senescence induction in salivary gland stem/progenitor cells after irradiation.MATERIALS AND METHODS: A dose of 7 Gy photons was used to irradiate mouse salivary gland organoids. Senescent markers and mitochondrial function were assessed using rt-qPCR, western blot analysis, SA-β-Gal staining and flow cytometry analysis. Mitochondrial dynamics-related proteins were detected by western blot analysis while Mdivi-1 and MFI8 were used to modulate the mitochondrial fission process. To induce mitophagy, organoids were treated with Urolithin A and PMI and subsequently stem/progenitor cell self-renewal capacity was assessed as organoid forming efficiency.RESULTS: Irradiation led to increased senescence and accumulation of dysfunctional mitochondria. This was accompanied by a strong downregulation of mitochondrial fission-related proteins and mitophagy-related genes. After irradiation, treatment with the mitophagy inducer Urolithin A attenuated the senescent phenotype and improved organoid growth and stem/progenitor cell self-renewal capacity.CONCLUSION: This study shows the important interplay between senescence and mitochondrial dysfunction after irradiation. Importantly, activation of mitophagy improved salivary gland stem/progenitor cell function thereby providing a novel therapeutic strategy to restore the regenerative capacity of salivary glands following irradiation.</p

Generation and Differentiation of Adult Tissue-Derived Human Thyroid Organoids

Total thyroidectomy as part of thyroid cancer treatment results in hypothyroidism requiring lifelong daily thyroid hormone replacement. Unbalanced hormone levels result in persistent complaints such as fatigue, constipation, and weight increase. Therefore, we aimed to investigate a patient-derived thyroid organoid model with the potential to regenerate the thyroid gland. Murine and human thyroidderived cells were cultured as organoids capable of self-renewal and which expressed proliferation and putative stem cell and thyroid characteristics, without a change in the expression of thyroid tumor-related genes. These organoids formed thyroid-tissue-resembling structures in culture. (Xeno-)transplantation of 600,000 dispersed organoid cells underneath the kidney capsule of a hypothyroid mouse model resulted in the generation of hormone-producing thyroid-resembling follicles. This study provides evidence that thyroid-lineagespecific cells can form organoids that are able to self-renew and differentiate into functional thyroid tissue. Subsequent (xeno-)transplantation of these thyroid organoids demonstrates a proof of principle for functional miniature gland formation

Parotid Gland Stem Cell Sparing Radiation Therapy for Patients With Head and Neck Cancer:A Double-Blind Randomized Controlled Trial

BACKGROUND: Radiotherapy for head and neck cancer (HNC) frequently leads to salivary gland damage and subsequent xerostomia. The radiation response of parotid glands of rats, mice, and patients critically depends on dose to its stem cells, mainly located in the gland's main ducts (stem cell rich (SCR) region). Therefore, this double-blind randomized controlled trial aimed to test the hypothesis that parotid gland stem cell sparing radiotherapy preserves parotid gland function better than currently-used whole parotid gland sparing radiotherapy. METHODS: HNC patients (n=102) treated with definitive radiotherapy were randomized between standard parotid sparing and stem cell sparing (SCS) techniques. The primary endpoint was >75% reduction in parotid gland saliva production compared to pretreatment production (FLOW12M). Secondary endpoints were several aspects of xerostomia 12 months after treatment. RESULTS: Fifty-four patients were assigned to the standard arm and 48 to the SCS arm. Only dose to the SCR regions (contralateral 16 and 11 Gy (p=0.004) and ipsilateral 26 and 16 Gy (p=0.001), standard and SCS arm respectively) and pretreatment patient-rated daytime xerostomia (35% and 13% (p=0.01), standard and SCS arm respectively) differed significantly between the arms. In the SCS arm, 1 patient (2.8%) experienced FLOW12M compared to 2 (4.9%) in the standard arm (p=1.00). However, a trend towards better relative parotid gland salivary function in favor of SCS radiotherapy was shown. Moreover, multivariable analysis showed that mean contralateral SCR region dose was the strongest dosimetric predictor for moderate-to-severe patient-rated daytime xerostomia and grade ≥2 physician-rated xerostomia, the latter including complaints of alteration in diet. CONCLUSIONS: No significant better parotid function was observed in SCS radiotherapy. However, additional multivariable analysis showed that dose to the SCR region was more predictive for development of parotid gland function related xerostomia endpoints, than dose to the entire parotid gland