Diverse progenitor cells preserve salivary gland ductal architecture after radiation induced damage

May, Alison J.; Pacheco, Noel Cruz; Emmerson, Elaine; Siedel, Kerstin; Nathan, Sara; Muench, Marcus O.; Klein, Ophir D.; Knox, Sarah M.

doi:10.1101/295501

Cited by 18 publications

(36 citation statements)

References 33 publications

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“…SGPCs maintain SG homeostasis by proliferation and differentiation [ 11 ]. The BSD is a proposed niche of SGPCs, and is easily identifiable histologically [ 12–14 ]. p16 + BSD and total epithelial cells in pSS significantly increased compared with non-SS sicca control patients.…”

Section: Discussionmentioning

confidence: 99%

“…The basal striated duct (BSD) layer has been proposed to represent a progenitor cell niche in SG [ 11 ]. SG progenitor cells (SGPCs) that potentially reside in this niche maintain SG homeostasis by self-renewal and differentiation into other terminal and functional cell types in SGs, namely saliva producing acinar cells, saliva modifying ductal cells and myoepithelial cells [ 12 – 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Progenitor cell niche senescence reflects pathology of the parotid salivary gland in primary Sjögren’s syndrome

et al. 2020

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Objective Salivary gland (SG) progenitor cells (SGPCs) maintain SG homeostasis. We have previously shown that in primary Sjögren’s syndrome (pSS), SGPCs are likely to be senescent, and may underpin SG dysfunction. This study assessed the extent of senescence of cells in a SGPC niche in pSS patients’ SGs, and its correlation with functional and clinical parameters. Methods The expression of p16 and p21 as markers of senescence in both total SG epithelium and a SGPC niche (basal striated duct cells, BSD) was examined in SGs of pSS (n = 35), incomplete pSS (n = 13) (patients with some signs of pSS, but not fulfilling all classification criteria) and non-SS sicca control (n = 21) patients. This was correlated with functional and clinical parameters. Results pSS patient SGs contained significantly more p16+ cells both in the epithelium in general (P <0.01) and in the BSD layer (P <0.001), than non-SS SGs. Significant correlations were found in pSS patients between p16+ BSD cells and secretion of unstimulated whole saliva, stimulated whole saliva, stimulated parotid saliva, CD45+ infiltrate, ultrasound total score and ACR-EULAR classification score, but not with EULAR Sjögren’s syndrome disease activity index (ESSDAI) and EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) scores. Correlations with total epithelium p16+ cells were weaker. Incomplete pSS patients also had increased numbers of p16+ epithelial and BSD cells. Based on protein and mRNA expression, p21+ appears not to play a significant role in the SG in pSS. Conclusion These findings suggest SGPC senescence may be an early feature of primary Sjögren’s syndrome and may contribute to defective SG function in pSS but not to systemic disease activity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Progenitor cell niche senescence reflects pathology of the parotid salivary gland in primary Sjögren’s syndrome

et al. 2020

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“…We next searched for co-expression of selected genes in the mouse brain by histological methods. We chose the Kit gene for immunohistochemical analysis as highly specific antibodies for the cKit receptor are available ( May et al , 2018 ) and determined that virtually all PV-immunopositive neurons were also cKit-positive in the mouse ST. On the other hand, only a small proportion of striatal cKit-positive cells were PV-negative ( Fig. 5A; Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Molecular targets for endogenous glial cell line-derived neurotrophic factor modulation in striatal parvalbumin interneurons

Enterría‐Morales

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Blesa

et al. 2020

Brain Communications

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Administration of recombinant glial cell line-derived neurotrophic factor (GDNF) into the putamen has been tested in preclinical and clinical studies to evaluate its neuroprotective effects on the progressive dopaminergic neuronal degeneration that characterises Parkinson’s disease. However, intracerebral GDNF infusion is a challenging therapeutic strategy, with numerous potential technical and medical limitations. Most of these limitations could be avoided if the production of endogenous GDNF could be increased. GDNF is naturally produced in the striatum from where it exerts a trophic action on the nigrostriatal dopaminergic pathway. Most of striatal GDNF is synthesized by a subset of GABAergic interneurons characterised by the expression of parvalbumin. We sought to identify molecular targets specific to those neurons and which are putatively associated with GDNF synthesis. To this end, the transcriptomic differences between GDNF-positive parvalbumin neurons in the striatum and parvalbumin neurons located in the nearby cortex, which do not express GDNF, were analysed. Using mouse reporter models, we have defined the genomic signature of striatal parvalbumin interneurons obtained by fluorescence-activated cell sorting followed by microarray comparison. Short-listed genes were validated by additional histological and molecular analyses. These genes code for membrane receptors (Kit, Gpr83, Tacr1, Tacr3, Mc3r), cytosolic proteins (Pde3a, Crabp1, Rarres2, Moxd1), and a transcription factor (Lhx8). We also found the proto-oncogene cKit to be highly specific of parvalbumin interneurons in the nonhuman primate striatum, thus highlighting a conserved expression between species and suggesting that specific genes identified in mouse parvalbumin neurons could be putative targets in the human brain. Pharmacological stimulation of four G-protein coupled receptors enriched in the striatal parvalbumin interneurons inhibited Gdnf expression presumably by decreasing cyclic adenosine monophosphate formation. Additional experiments with pharmacological modulators of adenylyl cyclase and protein kinase A indicated that this pathway is a relevant intracellular route to induce Gdnf gene activation. This preclinical study is an important step in the ongoing development of a specific pro-endo-GDNF pharmacological strategy to treat Parkinson’s disease.

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“…Lineage tracing has been used to determine the in vivo potential of several proposed stem cell populations in the adult salivary glands . Under normal physiological conditions, the proposed K5‐expressing and K14‐expressing stem cell populations labeled only duct cells . However, K14 cells undergo continuous cycling in vivo, contribute to differentiated cells in the granular ducts, and retain label after 28 weeks, indicating that they are a lineage‐restricted unipotent stem cell population .…”

Section: In Vivo Lineage Tracingmentioning

confidence: 99%

“…However, K14 cells undergo continuous cycling in vivo, contribute to differentiated cells in the granular ducts, and retain label after 28 weeks, indicating that they are a lineage‐restricted unipotent stem cell population . Lineage tracing also revealed that potential stem cells expressing c‐KIT and Wnt‐responsive Axin2 are restricted to generating duct cells in adult. In contrast to these results, lineage tracing of p63‐positive cells, which contribute to all salivary gland cell lineages during embryonic development, labeled a small number of acinar cells, in addition to duct and myoepithelial cells .…”

Section: In Vivo Lineage Tracingmentioning

confidence: 99%

Concise Review: A Critical Evaluation of Criteria Used to Define Salivary Gland Stem Cells

2019

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In the effort to develop cell-based therapies to treat salivary gland dysfunction, many different populations of cells in the adult salivary glands have been proposed as stem cells. These cell populations vary, depending on the assay used, and are often nonoverlapping, leading to the conclusion that salivary glands harbor multiple stem cells. The goal of this review is to critically appraise the assays and properties used to identify stem cells in the adult salivary gland, and to consider the caveats of each. Re-evaluation of the defining criteria may help to reconcile the many potential stem cell populations described in the salivary gland, in order to increase comparability between studies and build consensus in the field.A number of diverse and nonoverlapping cell populations have been designated as adult stem cells in the salivary glands. The present study is focused on the criteria used to define these cell populations and highlights the limitations associated with each. A critical re-evaluation of how the various cell populations were characterized may serve to clarify which cells may be useful for regenerative therapy.

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Diverse progenitor cells preserve salivary gland ductal architecture after radiation induced damage

Cited by 18 publications

References 33 publications

Progenitor cell niche senescence reflects pathology of the parotid salivary gland in primary Sjögren’s syndrome

Progenitor cell niche senescence reflects pathology of the parotid salivary gland in primary Sjögren’s syndrome

Molecular targets for endogenous glial cell line-derived neurotrophic factor modulation in striatal parvalbumin interneurons

Concise Review: A Critical Evaluation of Criteria Used to Define Salivary Gland Stem Cells

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