IFNγ and TNFα optimize salivary gland mesenchymal stromal cells: an alternative to marrow- and adipose-MSCs for radiation xerostomia.

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Local mesenchymal stromal cell (MSC) administration is a promising therapy for xerostomia. MSCs deploy their advantageous effects through their trophic secretome and immunomodulatory capabilities. These functions are enhanced with IFNγ pre-licensing, but the effects of TNFα pre-licensing are unknown. Our objective was to compare MSCs by tissue source (MSC(BM), MSC(AD), and salivary gland-derived [MSC(SG)]) and by cytokine pre-licensing conditions. We used single cell and bulk RNA sequencing and ELISA to determine key trophic and immunomodulatory features differing between human MSC(BM), MSC(AD), and MSC(SG). We used ELISA and flow cytometry of T-cell co-culture to define the effect of IFNγ and/or TNFα on MSC trophic secretome and immunomodulatory capacity. Finally, we studied salivary flow and glandular recovery with MSC injection in radiation-induced xerostomia mice. Bulk RNA sequencing (RNAseq) of MSC(BM), MSC(AD), and MSC(SG) revealed that they shared 85 % of transcripts. Key differences included extracellular matrix production and response to cytokines in MSC(SG). Single cell RNA sequencing showed MSC(SG) treated with IFNγ and TNFα transcriptionally diverged from other treatment conditions. Regardless of MSC source, dual stimulation of MSCs with IFNγ and TNFα produced an average of more than a 20-fold increase in R-Spondin 3 compared to vehicle conditions. Additionally, IFN

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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