scholarly journals Laminin-1 Peptides Conjugated to Fibrin Hydrogels Promote Salivary Gland Regeneration in Irradiated Mouse Submandibular Glands

2021 ◽  
Vol 9 ◽  
Author(s):  
Kihoon Nam ◽  
Harim T. dos Santos ◽  
Frank Maslow ◽  
Bryan G. Trump ◽  
Pedro Lei ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Salivary Gland ◽  
Salivary Glands ◽  
Tissue Regeneration ◽  
Secretory Function ◽  
Gland Morphogenesis ◽  
Salivary Gland Regeneration ◽  
Laminin 1

Previous studies demonstrated that salivary gland morphogenesis and differentiation are enhanced by modification of fibrin hydrogels chemically conjugated to Laminin-1 peptides. Specifically, Laminin-1 peptides (A99: CGGALRGDN-amide and YIGSR: CGGADPGYIGSRGAA-amide) chemically conjugated to fibrin promoted formation of newly organized salivary epithelium both in vitro (e.g., using organoids) and in vivo (e.g., in a wounded mouse model). While these studies were successful, the model’s usefulness for inducing regenerative patterns after radiation therapy remains unknown. Therefore, the goal of the current study was to determine whether transdermal injection with the Laminin-1 peptides A99 and YIGSR chemically conjugated to fibrin hydrogels promotes tissue regeneration in irradiated salivary glands. Results indicate that A99 and YIGSR chemically conjugated to fibrin hydrogels promote formation of functional salivary tissue when transdermally injected to irradiated salivary glands. In contrast, when left untreated, irradiated salivary glands display a loss in structure and functionality. Together, these studies indicate that fibrin hydrogel-based implantable scaffolds containing Laminin-1 peptides promote secretory function of irradiated salivary glands.

scholarly journals Regenerating Salivary Glands in the Microenvironment of Induced Pluripotent Stem Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Hitomi Ono ◽  
Aya Obana ◽  
Yu Usami ◽  
Manabu Sakai ◽  
Kanji Nohara ◽  
...  
Keyword(s):  
Stem Cells ◽  
Salivary Gland ◽  
Salivary Glands ◽  
Ips Cells ◽  
Initial Attempt ◽  
Cell Niche ◽  
Salivary Gland Regeneration ◽  
Induced Pluripotent

This report describes our initial attempt to regenerate salivary glands using induced pluripotent stem (iPS) cellsin vivoandin vitro. Glandular tissues that were similar to the adult submandibular glands (SMGs) and sublingual glands could be partially produced by the transplantation of iPS cells into mouse salivary glands. However, the tumorigenicity of iPS cells has not been resolved yet. It is well known that stem cells affect their microenvironment, known as a stem cell niche. We focused on the niche and the interaction between iPS cells and salivary gland cells in our study on salivary gland regeneration. Coculture of embryonic SMG cells and iPS cells have better-developed epithelial structures and fewer undifferentiated specific markers than monoculture of embryonic SMG cellsin vitro. These results suggest that iPS cells have a potential ability to accelerate differentiation for salivary gland development and regeneration.

scholarly journals Salivary Gland Tissue Engineering Approaches: State of the Art and Future Directions

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1723
Author(s):  
Lindsay R. Piraino ◽  
Danielle S. W. Benoit ◽  
Lisa A. DeLouise
Keyword(s):  
Tissue Engineering ◽  
Salivary Gland ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Secretory Function ◽  
Aquaporin 5 ◽  
Soluble Factors

Salivary gland regeneration is important for developing treatments for radiation-induced xerostomia, Sjögren’s syndrome, and other conditions that cause dry mouth. Culture conditions adopted from tissue engineering strategies have been used to recapitulate gland structure and function to study and regenerate the salivary glands. The purpose of this review is to highlight current trends in the field, with an emphasis on soluble factors that have been shown to improve secretory function in vitro. A PubMed search was conducted to identify articles published in the last 10 years and articles were evaluated to identify the most promising approaches and areas for further research. Results showed increasing use of extracellular matrix mimetics, such as Matrigel®, collagen, and a variety of functionalized polymers. Soluble factors that provide supportive cues, including fibroblast growth factors (FGFs) and neurotrophic factors, as well as chemical inhibitors of Rho-associated kinase (ROCK), epidermal growth factor receptor (EGFR), and transforming growth factor β receptor (TGFβR) have shown increases in important markers including aquaporin 5 (Aqp5); muscle, intestine, and stomach expression 1 (Mist1); and keratin (K5). However, recapitulation of tissue function at in vivo levels is still elusive. A focus on identification of soluble factors, cells, and/or matrix cues tested in combination may further increase the maintenance of salivary gland secretory function in vitro. These approaches may also be amenable for translation in vivo to support successful regeneration of dysfunctional glands.

scholarly journals Sox9+ Cell is Required for Salivary Gland Regeneration after Radiation Damage via Wnt/β-Catenin Pathway

2021 ◽  
Author(s):  
Xiuyun Xu ◽  
Xiong Gan ◽  
Ming Zhang ◽  
Jiaxiang Xie ◽  
Shuang Chen ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Salivary Glands ◽  
Cell Lineage ◽  
Term Treatment ◽  
Sequencing Data ◽  
Long Term Treatment ◽  
Radiation Induced ◽  
Gland Function ◽  
Salivary Gland Regeneration

Abstract Background: Radiotherapy for head and neck cancer can cause serious side effects, including severe damage to the salivary glands, resulting in symptoms such as xerostomia, dental caries, oral infectious and so on. Due to lack of long-term treatment for the symptoms of saliva barren, current research has focused on finding endogenous stem cells that can differentiate into various cell lineage to replace lost tissue and restore function. Results: In our study, we identified Sox9+ cells can differentiate into various salivary epithelial cell lineages under homeostatic conditions. After ablating Sox9+ cells, the salivary glands of irradiated mice showed more severe phenotypes and reduced proliferative capacity. Analysis of online single cell RNA-sequencing data revealed enrichment of the Wnt/β-catenin pathway in Sox9+ cell population. Furthermore, treatment of Wnt/β-catenin inhibitor to irradiated mice inhibited the regenerative capability of Sox9+ cells. Finally, we showed that Sox9+ cells were able to form organoids in vitro and transplanting these organoids into salivary glands after radiation restored part of salivary gland function. Conclusions: In short, our research indicated that regenerative therapy targeting Sox9+ cells is a promising method to solve the radiation induced salivary gland injury.

scholarly journals The murine cytomegalovirus MCK-2 facilitates in vivo infection transfer from dendritic cells to salivary gland acinar cells.

2021 ◽  
Author(s):  
Jiawei Ma ◽  
Kimberley Bruce ◽  
Philip G. Stevenson ◽  
Helen E. Farrell
Keyword(s):  
Dendritic Cells ◽  
Salivary Gland ◽  
Epithelial Cells ◽  
Salivary Glands ◽  
Immune Evasion ◽  
Acinar Cells ◽  
Lung Infection ◽  
Human Cmv

The cytomegaloviruses (CMVs) spread systemically via myeloid cells and demonstrate a broad tissue tropism. Human CMV (HCMV) UL128 encodes a component of the virion pentameric complex (PC) that is important for entry into epithelial cells and cell-cell spread in vitro . It possesses N-terminal amino acid sequences similar to C-C chemokines. While the species-specificity of HCMV precludes confirmation of UL128 function in vivo , UL128-like counterparts in experimental animals have demonstrated a role for salivary gland infection. How they achieve this has not been defined, although effects on monocyte tropism and immune evasion have been proposed. By tracking infected cells following lung infection, we show that although the UL128-like protein in mouse CMV (MCMV; designated MCK-2), facilitated entry into lung macrophages, it was dispensable for subsequent viremia mediated by CD11c + dendritic cells (DC) and extravasation to the salivary glands. Notably, MCK-2 was important for transfer of MCMV infection from DC to salivary gland acinar epithelial cells. Acinar cell infection of MCMVs deleted of MCK-2 was not rescued by T-cell depletion, arguing against an immune evasion mechanism for MCK-2 in the salivary glands. In contrast to lung infection, peritoneal MCMV inoculation yields a mixed monocyte/DC viremia. In this setting, MCK-2 again promoted DC-dependent infection of salivary gland acinar cells, but it was not required for monocyte-dependent spread to the lung. Thus, the action of MCK-2 in MCMV spread was specific to DC-acinar cell interaction. IMPORTANCE Cytomegaloviruses (CMVs) establish myeloid cell-associated viremias and persistent shedding from the salivary glands. In vitro studies with human CMV (HCMV) have implicated HCMV UL128 in epithelial tropism, but its role in vivo is unknown. Here we analysed how a murine CMV (CMV) protein with similar physical properties - designated MCK-2 - contributes to host colonization. We demonstrate that MCK-2 is dispensable for the initial systemic spread from primary infection sites, but within the salivary gland facilitates transfer of infection from dendritic cells (DC) to epithelial acinar cells. Virus transfer from extravasated monocytes to the lungs did not require MCK-2, indicating a tissue-specific effect. These results provide new information about how persistent viral tropism determinants operate in vivo .

The value of the twinkling artefact for the diagnosis of sialolithiasis of the large salivary glands

2017 ◽  
Vol 132 (2) ◽  
pp. 162-167 ◽  
Author(s):  
G Pabst ◽  
K Strobel ◽  
J Zehnder
Keyword(s):  
Salivary Gland ◽  
Salivary Glands ◽  
Doppler Ultrasound ◽  
Model Test ◽  
Power Doppler ◽  
Intensity Level ◽  
Colour Doppler

AbstractObjective:The imaging of stones in the salivary glands and ducts poses a challenge, even to experienced ultrasound examiners. This study investigated whether the ‘twinkling artefact’, which occurs at internal calcific foci during Doppler ultrasound examinations, is useful for detecting salivary gland stones.Methods:In a model test, 20 salivary stones were analysedin vitro, via Doppler ultrasound, with regard to their representability and the triggering of the twinkling artefact. In a follow-up study, 28 patients with sialolithiasis and food-related large salivary gland swellings were examined, using both power and colour Doppler modes, with regard to the twinkling artefact. All ultrasound examinations were performed by an experienced examiner and retrospectively graded by two experienced sonographers.Results:All stones could reliably be detected using the twinkling artefact in the model test. Twenty-seven of 28 salivary stones (96 per cent) also showed twinklingin vivo, during patient assessment. The power Doppler mode showed a significantly higher intensity level of twinkling than the colour Doppler mode (p< 0.0001).Conclusion:The twinkling artefact is a very reliable sign for the diagnosis of sialolithiasis. Power Doppler is superior to colour Doppler for detection of the twinkling artefact.

scholarly journals Three-Dimensional Bioprinting Nanotechnologies towards Clinical Application of Stem Cells and Their Secretome in Salivary Gland Regeneration

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Joao N. Ferreira ◽  
Sasitorn Rungarunlert ◽  
Ganokon Urkasemsin ◽  
Christabella Adine ◽  
Glauco R. Souza
Keyword(s):  
Salivary Gland ◽  
Ex Vivo ◽  
Three Dimensional ◽  
Cell Types ◽  
Poor Quality ◽  
Saliva Secretion ◽  
Wide Range ◽  
Salivary Gland Regeneration

Salivary gland (SG) functional damage and severe dry mouth (or xerostomia) are commonly observed in a wide range of medical conditions from autoimmune to metabolic disorders as well as after radiotherapy to treat specific head and neck cancers. No effective therapy has been developed to completely restore the SG functional damage on the long-term and reverse the poor quality of life of xerostomia patients. Cell- and secretome-based strategies are currently being tested in vitro and in vivo for the repair and/or regeneration of the damaged SG using (1) epithelial SG stem/progenitor cells from salispheres or explant cultures as well as (2) nonepithelial stem cell types and/or their bioactive secretome. These strategies will be the focus of our review. Herein, innovative 3D bioprinting nanotechnologies for the generation of organotypic cultures and SG organoids/mini-glands will also be discussed. These bioprinting technologies will allow researchers to analyze the secretome components and extracellular matrix production, as well as their biofunctional effects in 3D mini-glands ex vivo. Improving our understanding of the SG secretome is critical to develop effective secretome-based therapies towards the regeneration and/or repair of all SG compartments for proper restoration of saliva secretion and flow into the oral cavity.

Decellularized bone extracellular matrix in skeletal tissue engineering

2020 ◽  
Vol 48 (3) ◽  
pp. 755-764
Author(s):  
Benjamin B. Rothrauff ◽  
Rocky S. Tuan
Keyword(s):  
Tissue Engineering ◽  
Bone Regeneration ◽  
Tissue Regeneration ◽  
Animal Studies ◽  
Tumor Resection ◽  
Regenerative Capacity ◽  
Skeletal Tissue ◽  
Large Bone

Bone possesses an intrinsic regenerative capacity, which can be compromised by aging, disease, trauma, and iatrogenesis (e.g. tumor resection, pharmacological). At present, autografts and allografts are the principal biological treatments available to replace large bone segments, but both entail several limitations that reduce wider use and consistent success. The use of decellularized extracellular matrices (ECM), often derived from xenogeneic sources, has been shown to favorably influence the immune response to injury and promote site-appropriate tissue regeneration. Decellularized bone ECM (dbECM), utilized in several forms — whole organ, particles, hydrogels — has shown promise in both in vitro and in vivo animal studies to promote osteogenic differentiation of stem/progenitor cells and enhance bone regeneration. However, dbECM has yet to be investigated in clinical studies, which are needed to determine the relative efficacy of this emerging biomaterial as compared with established treatments. This mini-review highlights the recent exploration of dbECM as a biomaterial for skeletal tissue engineering and considers modifications on its future use to more consistently promote bone regeneration.

scholarly journals The Radiation-Induced Regenerative Response of Adult Tissue-Specific Stem Cells: Models and Signaling Pathways

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 855
Author(s):  
Paola Serrano Martinez ◽  
Lorena Giuranno ◽  
Marc Vooijs ◽  
Robert P. Coppes
Keyword(s):  
Signaling Pathways ◽  
Progenitor Cells ◽  
Tissue Regeneration ◽  
Normal Tissue ◽  
Cellular Response ◽  
Adult Tissue ◽  
Tissue Specific ◽  
Radiation Induced

Radiotherapy is involved in the treatment of many cancers, but damage induced to the surrounding normal tissue is often inevitable. Evidence suggests that the maintenance of homeostasis and regeneration of the normal tissue is driven by specific adult tissue stem/progenitor cells. These tasks involve the input from several signaling pathways. Irradiation also targets these stem/progenitor cells, triggering a cellular response aimed at achieving tissue regeneration. Here we discuss the currently used in vitro and in vivo models and the involved specific tissue stem/progenitor cell signaling pathways to study the response to irradiation. The combination of the use of complex in vitro models that offer high in vivo resemblance and lineage tracing models, which address organ complexity constitute potential tools for the study of the stem/progenitor cellular response post-irradiation. The Notch, Wnt, Hippo, Hedgehog, and autophagy signaling pathways have been found as crucial for driving stem/progenitor radiation-induced tissue regeneration. We review how these signaling pathways drive the response of solid tissue-specific stem/progenitor cells to radiotherapy and the used models to address this.

scholarly journals Design of PSMA ligands with modifications at the inhibitor part: an approach to reduce the salivary gland uptake of radiolabeled PSMA inhibitors?

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Veronika Barbara Felber ◽  
Manuel Amando Valentin ◽  
Hans-Jürgen Wester
Keyword(s):  
Salivary Gland ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
In Vivo Studies ◽  
Tumor Xenograft ◽  
Tumor Uptake ◽  
Lncap Cells ◽  
High Affinity

Abstract Aim To investigate whether modifications of prostate-specific membrane antigen (PSMA)-targeted radiolabeled urea-based inhibitors could reduce salivary gland uptake and thus improve tumor-to-salivary gland ratios, several analogs of a high affinity PSMA ligand were synthesized and evaluated in in vitro and in vivo studies. Methods Binding motifs were synthesized ‘on-resin’ or, when not practicable, in solution. Peptide chain elongations were performed according to optimized standard protocols via solid-phase peptide synthesis. In vitro experiments were performed using PSMA+ LNCaP cells. In vivo studies as well as μSPECT/CT scans were conducted with male LNCaP tumor xenograft-bearing CB17-SCID mice. Results PSMA ligands with A) modifications within the central Zn2+-binding unit, B) proinhibitor motifs and C) substituents & bioisosteres of the P1′-γ-carboxylic acid were synthesized and evaluated. Modifications within the central Zn2+-binding unit of PSMA-10 (Glu-urea-Glu) provided three compounds. Thereof, only natLu-carbamate I (natLu-3) exhibited high affinity (IC50 = 7.1 ± 0.7 nM), but low tumor uptake (5.31 ± 0.94% ID/g, 1 h p.i. and 1.20 ± 0.55% ID/g, 24 h p.i.). All proinhibitor motif-based ligands (three in total) exhibited low binding affinities (> 1 μM), no notable internalization and very low tumor uptake (< 0.50% ID/g). In addition, four compounds with P1′-ɣ-carboxylate substituents were developed and evaluated. Thereof, only tetrazole derivative natLu-11 revealed high affinity (IC50 = 16.4 ± 3.8 nM), but also this inhibitor showed low tumor uptake (3.40 ± 0.63% ID/g, 1 h p.i. and 0.68 ± 0.16% ID/g, 24 h p.i.). Salivary gland uptake in mice remained at an equally low level for all compounds (between 0.02 ± 0.00% ID/g and 0.09 ± 0.03% ID/g), wherefore apparent tumor-to-submandibular gland and tumor-to-parotid gland ratios for the modified peptides were distinctly lower (factor 8–45) than for [177Lu]Lu-PSMA-10 at 24 h p.i. Conclusions The investigated compounds could not compete with the in vivo characteristics of the EuE-based PSMA inhibitor [177Lu]Lu-PSMA-10. Although two derivatives (3 and 11) were found to exhibit high affinities towards LNCaP cells, tumor uptake at 24 h p.i. was considerably low, while uptake in salivary glands remained unaffected. Optimization of the established animal model should be envisaged to enable a clear identification of PSMA-targeting radioligands with improved tumor-to-salivary gland ratios in future studies.

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