Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, 1591639675, Iran.
Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
Pharmacol Rep. 2022 Aug;74(4):654-668. doi: 10.1007/s43440-022-00386-9. Epub 2022 Jul 17.
The immunomodulatory properties of mesenchymal stem cells (MSCs) have made them a prospective treatment option for inflammatory and autoimmune disorders. Recent studies have found an association between the immunomodulatory function of MSCs and Toll-like receptors (TLRs). Here, we investigated the effect of priming with lipopolysaccharide (LPS) as TLR4 ligand or polyinosinic:polycytidylic acid (poly I:C) as TLR3 ligand on the immunomodulatory function of adipose-derived MSCs (ADMSCs) in vitro and for the first time in an adjuvant-induced arthritis model (AIA).
ADMSCs were treated with LPS or poly I:C for 1 h. Splenocyte proliferation in the presence of primed ADMSCs was assessed in vitro using an MTT assay. Next, we investigated the therapeutic effect of primed ADMSCs in vivo. Male Wistar rats were infused with complete Freund's adjuvant (CFA) to develop arthritis and then intraperitoneally treated with not-primed, poly I:C- or LPS-primed ADMSCs. Clinical signs, histopathological alteration, and serum and spleen cytokine levels were analyzed.
Poly I:C-primed ADMSCs significantly reduced splenocytes proliferation, while ADMSCs primed with LPS increased splenocytes proliferation. Furthermore, poly I:C-primed ADMSCs significantly alleviated the clinical and histopathological severity and the secretion of inflammatory cytokines associated with Th17/Th1 such as IL-17 and IFN-γ. Poly I:C-primed ADMSCs also increased cytokines IL-10 and TGF-β. TNF-α and IL-6 Levels were also markedly diminished in the serum of AIA animals treated with poly I:C-primed ADMSCs. In contrast, priming ADMSCs with LPS significantly reduced the therapeutic effect of ADMSCs in AIA animals.
As a result of these findings, poly I:C priming may be a new technique for improving the therapeutic effects of MSCs in arthritic disorders.
间充质干细胞（MSCs）的免疫调节特性使其成为炎症和自身免疫性疾病的潜在治疗选择。最近的研究发现，MSCs 的免疫调节功能与 Toll 样受体（TLRs）之间存在关联。在这里，我们研究了用脂多糖（LPS）作为 TLR4 配体或聚肌苷酸：聚胞苷酸（poly I:C）作为 TLR3 配体预刺激对脂肪来源的间充质干细胞（ADMSCs）体外免疫调节功能的影响，这也是首次在佐剂诱导的关节炎模型（AIA）中进行研究。
用 LPS 或 poly I:C 处理 ADMSCs 1 小时。用 MTT 法检测预刺激的 ADMSCs 存在时脾细胞的增殖。接下来，我们研究了预刺激的 ADMSCs 的体内治疗效果。雄性 Wistar 大鼠用完全弗氏佐剂（CFA）输注以诱导关节炎，然后用未预刺激、poly I:C 或 LPS 预刺激的 ADMSCs 腹腔内治疗。分析临床症状、组织病理学改变以及血清和脾脏细胞因子水平。
poly I:C 预刺激的 ADMSCs 显著降低脾细胞增殖，而 LPS 预刺激的 ADMSCs 增加脾细胞增殖。此外，poly I:C 预刺激的 ADMSCs 显著减轻了临床和组织病理学严重程度以及与 Th17/Th1 相关的炎症细胞因子（如 IL-17 和 IFN-γ）的分泌。poly I:C 预刺激的 ADMSCs 还增加了细胞因子 IL-10 和 TGF-β。用 poly I:C 预刺激的 ADMSCs 治疗的 AIA 动物的血清中 TNF-α 和 IL-6 水平也明显降低。相比之下，用 LPS 预刺激 ADMSCs 显著降低了 AIA 动物中 ADMSCs 的治疗效果。
由于这些发现，poly I:C 预刺激可能是一种提高间充质干细胞在关节炎疾病中治疗效果的新技术。
