Abstract
Severe xerostomia (dry mouth) compromises the quality of life in patients with Sjögren’s syndrome or radiation therapy for head and neck cancer. A clinical management of xerostomia is often unsatisfactory as most interventions are palliative with limited efficacy. Following up our previous study demonstrating that mouse BM-MSCs are capable of differentiating into salivary epithelial cells in a co-culture system, we further explored the molecular basis that governs the MSC reprogramming by utilizing high-throughput iTRAQ-2D-LC-MS/MS-based proteomics. Our data revealed the novel induction of pancreas-specific transcription factor 1a (PTF1α), muscle, intestine and stomach expression-1 (MIST-1), and achaete-scute complex homolog 3 (ASCL3) in 7 day co-cultured MSCs but not in control MSCs. More importantly, a common notion of pancreatic-specific expression of PTF1 α was challenged for the first time by our verification of PTF1 α expression in the mouse salivary glands. Furthermore, a molecular network simulation of our selected putative MSC reprogramming factors demonstrated evidence for their perspective roles in salivary gland development. In conclusion, quantitative proteomics with extensive data analyses narrowed down a set of MSC reprograming factors potentially contributing to salivary gland regeneration. Identification of their differential/synergistic impact on MSC conversion warrants further investigation.
Highlights
Salivary glands (SGs) are irreversibly damaged by radiation therapy in patients with head and neck cancer or by autoreactive immune cells in Sjogren’s syndrome (SjS)
We reported that Bone marrow (BM)-mesenchymal stem cells (MSCs) differentiated into SG epithelial cells (SEC) when co-cultured with mouse Primary mouse Salivary Gland Cell (pSGC) in serum free-Hepato-STIM media without cell-to-cell contact
When we used a 95% cut-off value from three different sets, 1,844 distinct proteins were quantified as differentially expressed proteins (Raw data files were uploaded at PRIDE; http://www.ebi.ac.uk/pride/ archive; Project Accession: PXD002796) and matched against the Uniprot database (Uniprot_Mouse20130625.fasta) (Fig A in S1 File). 1844 proteins were subject to volcano plot analysis with a 30% cut-off value, which categorized 280 proteins (15.19%) as differentially expressed proteins in co-cultured MSCs compared to control MSCs
Summary
Salivary glands (SGs) are irreversibly damaged by radiation therapy in patients with head and neck cancer or by autoreactive immune cells in Sjogren’s syndrome (SjS). As a result of glandular damage, patients develop greatly diminished saliva production and feeling of dry mouth (xerostomia). The complications of dry mouth range from difficulty in speaking, swallowing, and eating, frequent fungal infections, rampant dental caries, and periodontal disease, all of which can significantly decrease the quality of life in patients [1]. There is no PLOS ONE | DOI:10.1371/journal.pone.0169677. Stem cell differentiation factors for salivary gland regeneration There is no PLOS ONE | DOI:10.1371/journal.pone.0169677 February 3, 2017
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