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Functional and histological evaluation of bone marrow stem cell-derived exosomes therapy on the submandibular salivary gland of diabetic Albino rats through TGF?/ Smad3 signaling pathway.

ABSTRACT: Background:To prevail over diabetes mellitus and its numerous complications, researchers are seeking new therapies. Exosomes are natural cargo of functional proteins and can be used as a therapeutic delivery of these molecules. Objective:The aim of this study was to evaluate the effect of exosomes derived from bone marrow mesenchymal stem cells (BM-MSCs) as a therapeutic intervention in salivary gland diabetic complications. Methods:Ten adult healthy male Albino rats, weighing about 150-200 g were grouped into 2 groups. Diabetic group I: consisted of 5 streptozotocin (STZ)-induced diabetic rats. Exosomes treated group II: consisted of 5 STZ-induced diabetic rats, each animal received a single injection of exosomes (100 ?g/kg/dose suspended in 0.2 ml PBS) through the tail vein. All animals were sacrificed after 5 weeks from the beginning of the experiment. Submandibular salivary gland samples were excised and processed for histological, ultrastructural examination and PCR for TGF?, Smad2 and Smad3. Blood glucose level was monitored weekly, salivary IgA and serum amylase were evaluated before and after diabetes induction and at the end of the experiment. Results:Histological and ultrastructural results of the exosomes treated group were promising regarding the glandular and ductal elements with less fibrosis observed. Results of PCR supported the role of exosomes to inhibit the diabetic sequalae in salivary gland and its complications through inhibiting TGF? and its related pathway via Smad2 and Smad3. Blood glucose levels were reduced. In addition, salivary glands' function was improved as evidenced by reduction in serum amylase and salivary IgA. Conclusion:BM-MSC-derived exosomes could be a novel therapeutic strategy for diabetic complications involving salivary glands.

SUBMITTER: AbuBakr N

PROVIDER: S-EPMC7203080 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Functional and histological evaluation of bone marrow stem cell-derived exosomes therapy on the submandibular salivary gland of diabetic Albino rats through TGFβ/ Smad3 signaling pathway.

AbuBakr Nermeen N Haggag Tahany T Sabry Dina D Salem Zeinab A ZA

Heliyon 20200420 4

<h4>Background</h4>To prevail over diabetes mellitus and its numerous complications, researchers are seeking new therapies. Exosomes are natural cargo of functional proteins and can be used as a therapeutic delivery of these molecules.<h4>Objective</h4>The aim of this study was to evaluate the effect of exosomes derived from bone marrow mesenchymal stem cells (BM-MSCs) as a therapeutic intervention in salivary gland diabetic complications.<h4>Methods</h4>Ten adult healthy male Albino rats, weigh ...[more]

PMID: 32382678

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Project description:BackgroundOrgan replacement regenerative therapy based on human adult stem cells may be effective for salivary gland hypofunction. However, the generated tissues are immature because the signaling factors that induce the differentiation of human salivary gland stem cells into salivary glands are unknown.MethodsIsolated human submandibular gland stem/progenitor cells (hSMGepiS/PCs) were characterized and three-dimensionally (3D) cultured to generate organoids and further induced by fibroblast growth factor 10 (FGF10) in vitro. The induced spheres alone or in combination with embryonic day 12.5 (E12.5) mouse salivary gland mesenchyme were transplanted into the renal capsules of nude mice to assess their development in vivo. Immunofluorescence, quantitative reverse transcriptase-polymerase chain reaction, calcium release analysis, western blotting, hematoxylin-eosin staining, Alcian blue-periodic acid-Schiff staining, and Masson's trichrome staining were performed to assess the structure and function of generated tissues in vitro and in vivo.ResultsThe isolated hSMGepiS/PCs could be long-term cultured with a stable genome. The organoids treated with FGF10 [FGF10 (+) group] exhibited higher expression of salivary gland-specific markers; showed spatial arrangement of AQP5+, K19+, and SMA+ cells; and were more sensitive to the stimulation by neurotransmitters than untreated organoids [FGF10 (-) group]. After heterotopic transplantation, the induced cell spheres combined with mouse embryonic salivary gland mesenchyme showed characteristics of mature salivary glands, including a natural morphology and saliva secretion.ConclusionFGF10 promoted the development of the hSMGepiS/PC-derived salivary gland organoids by the expression of differentiation markers, structure formation, and response to neurotransmitters in vitro. Moreover, the hSMGepiS/PCs responded to the niche in mouse embryonic mesenchyme and further differentiated into salivary gland tissues with mature characteristics. Our study provides a foundation for the regenerative therapy of salivary gland diseases.

Project description:Cleft formation during submandibular salivary gland branching morphogenesis is the critical step initiating the growth and development of the complex adult organ. Previous experimental studies indicated requirements for several epithelial cellular processes, such as proliferation, migration, cell-cell adhesion, cell-extracellular matrix (matrix) adhesion, and cellular contraction in cleft formation; however, the relative contribution of each of these processes is not fully understood since it is not possible to experimentally manipulate each factor independently. We present here a comprehensive analysis of several cellular parameters regulating cleft progression during branching morphogenesis in the epithelial tissue of an early embryonic salivary gland at a local scale using an on lattice Monte-Carlo simulation model, the Glazier-Graner-Hogeweg model. We utilized measurements from time-lapse images of mouse submandibular gland organ explants to construct a temporally and spatially relevant cell-based 2D model. Our model simulates the effect of cellular proliferation, actomyosin contractility, cell-cell and cell-matrix adhesions on cleft progression, and it was used to test specific hypotheses regarding the function of these parameters in branching morphogenesis. We use innovative features capturing several aspects of cleft morphology and quantitatively analyze clefts formed during functional modification of the cellular parameters. Our simulations predict that a low epithelial mitosis rate and moderate level of actomyosin contractility in the cleft cells promote cleft progression. Raising or lowering levels of contractility and mitosis rate resulted in non-progressive clefts. We also show that lowered cell-cell adhesion in the cleft region and increased cleft cell-matrix adhesions are required for cleft progression. Using a classifier-based analysis, the relative importance of these four contributing cellular factors for effective cleft progression was determined as follows: cleft cell contractility, cleft region cell-cell adhesion strength, epithelial cell mitosis rate, and cell-matrix adhesion strength.

Dataset Information

Functional and histological evaluation of bone marrow stem cell-derived exosomes therapy on the submandibular salivary gland of diabetic Albino rats through TGF?/ Smad3 signaling pathway.

Publications

Functional and histological evaluation of bone marrow stem cell-derived exosomes therapy on the submandibular salivary gland of diabetic Albino rats through TGFβ/ Smad3 signaling pathway.

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