Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Department of Medicine, University of Wisconsin Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, Wisconsin, USA.
Cytotherapy. 2021 Apr;23(4):301-310. doi: 10.1016/j.jcyt.2020.09.008. Epub 2020 Nov 28.
Mesenchymal stromal cells (MSCs) provide minor salivary glands (MSGs) with support and niche cells for epithelial glandular tissue. Little is known about resident MSG-derived MSCs (MSG-MSCs) in primary Sjӧgren's syndrome (PSS). The authors' objective is to define the immunobiology of endogenous PSS MSG-MSCs.
Using culture-adapted MSG-MSCs isolated from consenting PSS subjects (n = 13), the authors performed in vitro interrogation of PSS MSG-MSC immunobiology and global gene expression compared with controls. To this end, the authors performed phenotypic and immune functional analysis of indoleamine 2,3-dioxygenase (IDO), programmed death ligand 1 (PD-L1) and intercellular adhesion marker 1 (ICAM-1) before and after interferon γ (IFNγ) licensing as well as the effect of MSG-MSCs on T-cell proliferation. Considering the female predominance of PSS, the authors also addressed the influence of 17-β-estradiol on estrogen receptor α-positive-related MSC function.
The authors found that MSG-MSCs deployed normal immune regulatory functionality after IFNγ stimulation, as demonstrated by increased protein-level expression of IDO, PD-L1 and ICAM-1. The authors also found that MSG-MSCs suppressed T-cell proliferation in a dose-dependent manner independent of 17-β-estradiol exposure. Gene ontology and pathway analysis highlighted extracellular matrix deposition as a possible difference between PSS and control MSG-MSCs. MSG-MSCs demonstrated increased α-smooth muscle actin expression in PSS, indicating a partial myofibroblast-like adaptation.
These findings establish similar immune regulatory function of MSG-MSCs in both PSS and control patients, precluding intrinsic MSC immune regulatory defects in PSS. PSS MSG-MSCs show a partial imprinted myofibroblast-like phenotype that may arise in the setting of chronic inflammation, providing a plausible etiology for PSS-related glandular fibrosis.
间充质基质细胞 (MSCs) 为小唾液腺 (MSGs) 提供支持和巢细胞，以维持上皮腺组织。关于原发性干燥综合征 (PSS) 中小唾液腺来源的间充质基质细胞 (MSG-MSCs) 的了解甚少。作者的目的是定义内源性 PSS MSG-MSCs 的免疫生物学。
使用从同意的 PSS 受试者中分离的培养适应的 MSG-MSCs（n=13），作者进行了体外 PSS MSG-MSC 免疫生物学和全基因表达的探究，并与对照进行比较。为此，作者在干扰素 γ (IFNγ) 许可前后对吲哚胺 2,3-双加氧酶 (IDO)、程序性死亡配体 1 (PD-L1) 和细胞间黏附分子 1 (ICAM-1) 进行了表型和免疫功能分析，并研究了 MSG-MSCs 对 T 细胞增殖的影响。考虑到 PSS 女性居多，作者还研究了 17-β-雌二醇对雌激素受体 α 阳性相关 MSC 功能的影响。
作者发现，MSG-MSCs 在 IFNγ 刺激后表现出正常的免疫调节功能，表现为 IDO、PD-L1 和 ICAM-1 的蛋白水平表达增加。作者还发现，MSG-MSCs 以剂量依赖的方式抑制 T 细胞增殖，而与 17-β-雌二醇暴露无关。基因本体和通路分析突出了细胞外基质沉积作为 PSS 和对照 MSG-MSCs 之间的可能差异。在 PSS 中，MSG-MSCs 表现出较高的α-平滑肌肌动蛋白表达，表明其存在部分成肌纤维细胞样适应性。
这些发现确立了 PSS 和对照患者 MSG-MSCs 具有相似的免疫调节功能，排除了 PSS 中内在 MSC 免疫调节缺陷。PSS MSG-MSCs 表现出部分印记的成肌纤维细胞样表型，可能在慢性炎症的情况下出现，为 PSS 相关腺体纤维化提供了一个合理的病因。
