Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, Università degli Studi di Milano, Milan, Italy.
PhD Program in Experimental Medicine, Università degli Studi di Milano, Milan, Italy.
Stem Cells Transl Med. 2022 Sep 21;11(9):959-970. doi: 10.1093/stcltm/szac045.
Analytical advancements in lipidomics have enabled large-scale investigations of lipid biology. Herein, we focused on four bioactive lipid families, namely polyunsaturated fatty acids, eicosanoids, endocannabinoids, and N-acylethanolamines, and their involvement in the mesenchymal stem cells (MSC)-related inflammatory scenario. Since MSC secretome may represent a valid therapeutic alternative, here, the complete secretome and its vesicular component from adipose- and bone marrow-derived MSC and dermal fibroblasts were characterized by targeted mass spectrometry lipidomics. The 2-arachidonoylglycerol (2AG) and the palmitoylethanolamide (PEA), previously quantified in the MSC's secretome, were further investigated by assessing hypothetical effects in an in vitro model of osteoarthritis (OA) based on human primary articular chondrocytes (CH) stimulated with tumor necrosis factor alpha (TNFα). TNFα enhances the release of the inflammatory lipid prostaglandin E2 (PGE2), and an additional increment was observed when CH were treated with both TNFα and 2AG. In contrast, PEA downmodulates the PGE2 release to the levels of unstimulated CH suggesting a protective effect. TNFα also increases the expression of cyclooxygenase 2 (COX2), in particular when combined with 2AG, while PEA partly blunts TNFα-induced COX2 expression. In addition, TNFα-stimulated CH produce significantly higher levels of the inflammatory mediator nitric oxide (NO) both in the presence and in the absence of 2AG, and PEA was able to partially reduce NO release. Our results show a first partial lipidomic profile of MSC and DF secretome and suggest a possible implication of bioactive lipids in the OA scenario and in the future use of these cell-free products as innovative therapeutics.
脂质组学的分析进展使大规模研究脂质生物学成为可能。在这里，我们集中研究了四个生物活性脂质家族，即多不饱和脂肪酸、类花生酸、内源性大麻素和 N-酰基乙醇胺，以及它们在间充质干细胞（MSC）相关炎症中的作用。由于 MSC 分泌组可能代表一种有效的治疗替代物，因此，我们通过靶向质谱脂质组学对脂肪来源和骨髓来源的 MSC 和真皮成纤维细胞的完整分泌组及其囊泡成分进行了表征。此前在 MSC 分泌组中定量的 2-花生四烯酸甘油（2AG）和棕榈酰乙醇酰胺（PEA），通过评估基于 TNFα 刺激的人原代关节软骨细胞（CH）的体外骨关节炎（OA）模型中的假设作用进行了进一步研究。TNFα 增强了促炎脂质前列腺素 E2（PGE2）的释放，当 CH 同时用 TNFα 和 2AG 处理时，观察到额外的增加。相比之下，PEA 将 PGE2 释放降低到未刺激的 CH 的水平，提示具有保护作用。TNFα 还增加了环氧化酶 2（COX2）的表达，特别是当与 2AG 结合时，而 PEA 部分抑制了 TNFα 诱导的 COX2 表达。此外，TNFα 刺激的 CH 产生的炎症介质一氧化氮（NO）水平明显高于 2AG 的存在和不存在，PEA 能够部分减少 NO 的释放。我们的研究结果显示了 MSC 和 DF 分泌组的第一个部分脂质组学图谱，并表明生物活性脂质可能在 OA 情况下以及在将来将这些无细胞产物用作创新性治疗方法中的作用。
