University of Groningen and University Medical Center, Groningen, The Netherlands.
Bristol-Myers Squibb, Lawrence Township, New Jersey.
Arthritis Rheumatol. 2019 Jan;71(1):133-142. doi: 10.1002/art.40659.
A major characteristic of the autoimmune disease primary Sjögren's syndrome (SS) is salivary gland (SG) hypofunction. The inability of resident SG stem cells (SGSCs) to maintain homeostasis and saliva production has never been explained and limits our comprehension of mechanisms underlying primary SS. The present study was undertaken to investigate the role of salivary gland stem cells in hyposalivation in primary SS.
SGSCs were isolated from parotid biopsy samples from controls and patients classified as having primary SS or incomplete primary SS, according to the American College of Rheumatology/European League Against Rheumatism criteria. Self-renewal and differentiation assays were used to determine SGSC regenerative potential, RNA was extracted for sequencing analysis, single telomere length analysis was conducted to determine telomere length, and frozen tissue samples were used for immunohistochemical analysis.
SGSCs isolated from primary SS parotid gland biopsy samples were regeneratively inferior to healthy control specimens. We demonstrated that SGSCs from samples from patients with primary SS are not only lower in number and less able to differentiate, but are likely to be senescent, as revealed by telomere length analysis, RNA sequencing, and immunostaining. We further found that SGSCs exposed to primary SS-associated proinflammatory cytokines we induced to proliferate, express senescence-associated genes, and subsequently differentiate into intercalated duct cells. We also localized p16+ senescent cells to the intercalated ducts in primary SS SG tissue, suggesting a block in SGSC differentiation into acinar cells.
This study represents the first characterization of SGSCs in primary SS, and also the first demonstration of a linkage between an autoimmune disease and a parenchymal premature-aging phenotype. The knowledge garnered in this study indicates that disease-modifying antirheumatic drugs used to treat primary SS are not likely to restore saliva production, and should be supplemented with fresh SGSCs to recover saliva production.
自身免疫性疾病原发性干燥综合征（SS）的一个主要特征是唾液腺（SG）功能低下。常驻 SG 干细胞（SGSCs）无法维持体内平衡和唾液产生的能力从未得到解释，这限制了我们对原发性 SS 潜在机制的理解。本研究旨在探讨唾液腺干细胞在原发性 SS 低分泌中的作用。
根据美国风湿病学会/欧洲抗风湿病联盟标准，从对照者和分类为原发性 SS 或不完整原发性 SS 的患者的腮腺活检样本中分离 SGSCs。自我更新和分化测定用于确定 SGSC 的再生潜能，提取 RNA 进行测序分析，进行单个端粒长度分析以确定端粒长度，并使用冷冻组织样本进行免疫组织化学分析。
从原发性 SS 腮腺活检样本中分离的 SGSCs 的再生能力低于健康对照标本。我们证明，原发性 SS 患者样本中的 SGSCs 不仅数量较少且分化能力较弱，而且可能衰老，这是通过端粒长度分析、RNA 测序和免疫染色揭示的。我们进一步发现，SGSCs 暴露于原发性 SS 相关的促炎细胞因子中会诱导其增殖、表达衰老相关基因，随后分化为闰管细胞。我们还将 p16+衰老细胞定位于原发性 SS SG 组织中的闰管，表明 SGSC 分化为腺泡细胞受阻。
本研究代表了对原发性 SS 中 SGSCs 的首次表征，也是首次证明自身免疫性疾病与实质过早衰老表型之间存在关联。本研究获得的知识表明，用于治疗原发性 SS 的疾病修饰抗风湿药物不太可能恢复唾液分泌，应补充新鲜的 SGSCs 以恢复唾液分泌。
