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Mesenchymal treatment of the salivary glands upregulates proteins with regenerative potential in irradiated patients

ABSTRACT: Damage to the major salivary glands is the leading long-term side effect to radiation therapy in patients with head and neck cancerof radiation of head and neck cancers,. It resultresultsing in severe hyposalivationdry mouth , which profoundly impairs basic physiological functions for patients such as speaking, eating, tasting, and swallowing. TodayCurrently, no effective treatment can be offeredexists to alleviate radiation-induced hyposalivation, but recently, treatment with adipose tissue-derived mesenchymal stem/stromal cells (ASC) hasve very recently been tested as a newshowed potential treatment modalityfor restoring the function of the salivary glands. However, the impact of ASC-treatments on the salivary gland proteinome composition has notever been testedinvestigated. HereIn this study, we examine the salivary gland proteomeuse in patients with severe hyposalivation due to radiation therapy and in healthy controls using quantitative metaproteomics. Furthermore, to 1: compare the salivary proteome in patients with severe hyposalivation to that of healthy controls, and 2: towe addresslongitudinally monitorinvestigate the effect of ASC ASC-treatment on the salivary gland proteome. We identify that treatment with ASC-treatments results inis associated with the upregulation of specific proteins in saliva 120 days after injection. Therefore, oOur data findings suggest that ASCs to stimulate biological processes in the salivary gland tissue, which could have beneficial clinical effects.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Saliva

SUBMITTER: Rosa Jersie-Christensen

LAB HEAD: Rosa R. Jersie-Christensen

PROVIDER: PXD024152 | Pride | 2022-11-24

REPOSITORIES: Pride

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			Action	DRS
	20200623_MB_MWN_RosaRUC_01.pdResult	Other
	20200623_MB_MWN_RosaRUC_1ug_01.raw	Raw
	20200623_MB_MWN_RosaRUC_1ug_02.raw	Raw
	20200623_MB_MWN_RosaRUC_1ug_03.raw	Raw
	20200623_MB_MWN_RosaRUC_1ug_04.raw	Raw

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Project description:Severe hyposalivation often results from Sjögren’s syndrome or radiation therapy for head and neck cancer. Devastating consequences of hyposalivation, such as rampant dental caries and persistent oral candidiasis, compromise the quality of life in those patients. Clinical management for dry mouth typically involves simple palliative methods or secretagogues, which are designed to stimulate saliva secretion from residual salivary acinar cells present in the glands. However, direct interventions in chronic dryness have yet to be employed in the clinical setting. Despite numerous studies on salivary gland regeneration, the molecular basis governing stem cell transdifferentiation into salivary epithelial precursors (SEP) is largely unknown. Our previously published study clearly indicated mouse bone marrow-derived mesenchymal stem cells (BM-MSCs) can be differentiated into SEP in vitro when co-cultured with isolated primary salivary gland cells without cell-to-cell contact. Our current study utilized iTRAQ-LS-MS/MS-based quantitative proteomics to profile key regulatory factors involved in mouse MSC-to-SEP conversion. We identified 280 differentially expressed proteins in BM-MSCs over the course of 7 days of co-culture. Interestingly, protein expression of salivary transcription factors (STFs), such as transcription factor E2a (TCF3), high mobility group protein 20B (HMG20b), and ankyrin repeat domain-containing protein 56 (ANKRD56) were increased in a time-dependent manner. Notably, pancreas specific transcription factor 1a (PTF1α), muscle, intestine and stomach expression-1 (MIST-1) and achaete-scute complex homolog 3(ASCL3) were newly induced over time in differentiated MSCs. We also identified the expression of Ptf1α in the mouse salivary glands for the first time and verified its expression in independent batches of co-cultured MSCs by western blotting. Furthermore, simulation of the molecular network involving the identified STFs has demonstrated evidence for their perspective roles in salivary gland development during glandular maturation. Thus, our study provides the first extensive proteomic profile of MSC-to-SEP transdifferentiation and identifies novel STFs that may be critical for this process.

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Mesenchymal treatment of the salivary glands upregulates proteins with regenerative potential in irradiated patients

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