Experimental Animal Model Systems for Understanding Salivary Secretory Disorders

Kim, Ji-Youn; An, Chang-Hyeon; Jung, Jae‐Kwang

doi:10.3390/ijms21228423

Cited by 14 publications

(11 citation statements)

References 117 publications

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“…(*, **, and *** indicate p-values < 0.05, 0.005, and 0.0005, respectively. #, ##, and ### represent p-values < 5 x 10 -7 , 5 x 10 -10 , and 5 x 10 -13 , respectively).…”

Section: Resultsmentioning

confidence: 99%

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The Mayo Clinic Salivary Tissue-Organoid Biobanking: A Resource for Salivary Regeneration Research

Aalam,

Varela,

Khaderi

et al. 2024

Preprint

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The salivary gland (SG) is an essential organ that secretes saliva, which supports versatile oral function throughout life, and is maintained by elusive epithelial stem and progenitor cells (SGSPC). Unfortunately, aging, drugs, autoimmune disorders, and cancer treatments can lead to salivary dysfunction and associated health consequences. Despite many ongoing therapeutic efforts to mediate those conditions, investigating human SGSPC is challenging due to lack of standardized tissue collection, limited tissue access, and inadequate purification methods. Herein, we established a diverse and clinically annotated salivary regenerative biobanking at the Mayo Clinic, optimizing viable salivary cell isolation and clonal assays in both 2D and 3D-matrigel growth environments. Our analysis identified ductal epithelial cells in vitro enriched with SGSPC expressing the CD24/EpCAM/CD49f+ and PSMA- phenotype. We identified PSMA expression as a reliable SGSPC differentiation marker. Moreover, we identified progenitor cell types with shared phenotypes exhibiting three distinct clonal patterns of salivary differentiation in a 2D environment. Leveraging innovative label-free unbiased LC-MS/MS-based single-cell proteomics, we identified 819 proteins across 71 single cell proteome datasets from purified progenitor-enriched parotid gland (PG) and sub-mandibular gland (SMG) cultures. We identified distinctive co-expression of proteins, such as KRT1/5/13/14/15/17/23/76 and 79, exclusively observed in rare, scattered salivary ductal basal cells, indicating the potential de novo source of SGSPC. We also identified an entire class of peroxiredoxin peroxidases, enriched in PG than SMG, and attendant H2O2-dependent cell proliferation in vitro suggesting a potential role for PRDX-dependent floodgate oxidative signaling in salivary homeostasis. The distinctive clinical resources and research insights presented here offer a foundation for exploring personalized regenerative medicine.

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“…(*, **, and *** indicate p-values < 0.05, 0.005, and 0.0005, respectively. #, ##, and ### represent p-values < 5 x 10 -7 , 5 x 10 -10 , and 5 x 10 -13 , respectively).…”

Section: Resultsmentioning

confidence: 99%

“…E) Plot showing protein counts per cell of 10 most abundantly detected proteins in progenitor rich cells of PG relative to SMG (*, ** and *** indicate p-values < 0.05, 0.005 and 0.0005, respectively. #, ## and ### represent p-values < 5 x 10 -7 , 5 x 10 -10 and 5 x 10 -13 , respectively).…”

Section: Resultsmentioning

confidence: 99%

The Mayo Clinic Salivary Tissue-Organoid Biobanking: A Resource for Salivary Regeneration Research

Aalam,

Varela,

Khaderi

et al. 2024

Preprint

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show abstract

“…Similarly, we constructed a rat CS model by Wharton's duct PL via an intraoral approach to evaluate the redox status. Compared to the extraoral duct ligation, previous studies indicated that less glandular atrophy and slight residual secretory activity can be observed in the SMG (Kim et al, 2020; Osailan et al, 2006), possibly because of the non‐irritation of the parasympathetic chorda lingual nerve by the intraoral duct ligation. Additionally, partial duct obstruction such as duct stenosis and sialolith is generally believed to cause CS in patients (Li et al, 2018).…”

Section: Discussionmentioning

confidence: 98%

“…and slight residual secretory activity can be observed in the SMG (Kim et al, 2020;Osailan et al, 2006), possibly because of the nonirritation of the parasympathetic chorda lingual nerve by the intraoral duct ligation. Additionally, partial duct obstruction such as duct stenosis and sialolith is generally believed to cause CS in patients (Li et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Oxidative‐antioxidant imbalance in chronic sialadenitis of submandibular gland in human and rat

Liu

Wei

et al. 2021

Oral Diseases

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Chronic sialadenitis (CS) is a nonneoplastic disease that causes salivary dysfunction, mostly occurring in the submandibular gland (SMG) and parotid gland (Abdulkareem et al., 2018;Delli et al., 2014).Clinically, CS is mostly caused by salivary flow obstruction owing to sialolithiasis, gland inflammation, duct stenosis, external duct compression, mucus plugs or thick saliva sludge (Delagnes et al., 2017). The histopathological features of CS include acinar atrophy, ductal dilatation, ductal epithelial proliferation and metaplasia, lymphoplasmacytic infiltration, progressive fibrosis and intraductal mucous deposit (Hong et al., 2017). As CS is a common disorder in oral and maxillofacial surgery, and its exact pathological mechanism is largely unclear, it should be further explored by researchers.'Oxidative stress' (OS) refers to an imbalance between oxidants and antioxidants in favour of oxidants, leading to disruption of redox signalling and control and/or molecular damage (Sies et al., 2017). This generally results in the production of excessive reactive species that can damage proteins, lipids, nucleic acids and other biological molecular species in cells, resulting in mitochondrial dysfunction and

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“…SMG gland is the largest of three major salivary glands in rodents and is relatively more radiosensitive than PG (50,56,57), and therefore precision-radiation induced net loss in saliva may be due to higher loss of SMG function compared to PG or SLG. This is supported by more structural abnormalities in the SMG observed in our histological analysis.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Transgenic NSG-SGM3 Mouse Model of Precision Radiation-Induced Chronic Hyposalivation

et al. 2022

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Regenerative medicine holds promise to cure radiation-induced salivary hypofunction, a chronic side effect in patients with head and neck cancers, therefore reliable preclinical models for salivary regenerative outcome will promote progress towards therapies. In this study, our objective was to develop a cone beam computed tomography-guided precision ionizing radiation-induced preclinical model of chronic hyposalivation using immunodeficient NSG-SGM3 mice. Using a Schirmer's test based sialagogue-stimulated saliva flow kinetic measurement method, we demonstrated significant differences in hyposalivation specific to age, sex, precision-radiation dose over a chronic (6 months) timeline. NSG-SMG3 mice tolerated doses from 2.5 Gy up to 7.5 Gy. Interestingly, 5–7.5 Gy had similar effects on stimulated-saliva flow (∼50% reduction in young female at 6 months after precision irradiation over sham-treated controls), however, >5 Gy led to chronic alopecia. Different groups demonstrated characteristic saliva fluctuations early on, but after 5 months all groups nearly stabilized stimulated-saliva flow with low-inter-mouse variation within each group. Further characterization revealed precision-radiation-induced glandular shrinkage, hypocellularization, gland-specific loss of functional acinar and glandular cells in all major salivary glands replicating features of human salivary hypofunction. This model will aid investigation of human cell-based salivary regenerative therapies.

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Experimental Animal Model Systems for Understanding Salivary Secretory Disorders

Cited by 14 publications

References 117 publications

The Mayo Clinic Salivary Tissue-Organoid Biobanking: A Resource for Salivary Regeneration Research

The Mayo Clinic Salivary Tissue-Organoid Biobanking: A Resource for Salivary Regeneration Research

Oxidative‐antioxidant imbalance in chronic sialadenitis of submandibular gland in human and rat

Characterization of Transgenic NSG-SGM3 Mouse Model of Precision Radiation-Induced Chronic Hyposalivation

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