OBJECTIVE: A major characteristic of the autoimmune disease primary Sjögren's syndrome (pSS) is salivary gland (SG) hypofunction. Resident salivary gland stem cell (SGSC) inability to maintain homeostasis and saliva production has never been explained, and limits our comprehension of mechanisms underpinning pSS.
METHODS: SGSCs were isolated from parotid biopsies of controls and patients classified as pSS or incomplete pSS, according to ACR-EULAR criteria. Self-renewal and differentiation assays determined SGSC regenerative potential, RNA was extracted for RNASeq analysis, STELA analysis employed to determine telomere length, and frozen tissue used for immunohistochemical analysis.
RESULTS: Here we show that SGSCs isolated from pSS parotid gland biopsies are regeneratively inferior to healthy controls. We demonstrate that SGSCs from pSS biopsies are not only lower in number and less able to differentiate, but are likely to be senescent, as revealed by telomere length analysis, RNASeq and immunostaining. We further report that SGSCs exposed to pSS-associated proinflammatory cytokines are induced to proliferate, express senescence associated genes, and subsequently differentiate into intercalated duct cells. We also localize p16+ senescent cells to the intercalated ducts in pSS SG tissue, suggesting a block in SGSC differentiation into acinar cells.
CONCLUSION: This study represents the first characterization of SGSCs in pSS, and also the first linkage between an autoimmune disease and a parenchymal premature ageing phenotype. The knowledge garnered in this study argues that disease modifying anti-rheumatic drugs used to treat pSS are not likely to restore saliva production, but should be supplemented with fresh SGSCs to recover saliva production. This article is protected by copyright. All rights reserved.
- MESSENGER-RNA EXPRESSION
- EX-VIVO EXPANSION