Caffarini Miriam, Armeni Tatiana, Pellegrino Pamela, Cianfruglia Laura, Martino Marianna, Offidani Annamaria, Di Benedetto Giovanni, Arnaldi Giorgio, Campanati Anna, Orciani Monia
Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona, Italy.
Section of Biochemistry, Department of Clinical Sciences, Biology and Physics, Università Politecnica delle Marche, Ancona, Italy.
Front Cell Dev Biol. 2019 Oct 9;7:227. doi: 10.3389/fcell.2019.00227. eCollection 2019.
Cushing syndrome (CS), caused by glucocorticoid (GCs) excess, is strictly connected to onset of different metabolic diseases and impaired wound healing. The source of excessively high levels of GCs allows the identification of endogenous and exogenous (iatrogenic) CS. Iatrogenic patients usually receive also anti-metabolites serving as the foundation to modern steroid-sparing immunosuppressive therapy. Tissues mainly targeted by CS are bone and fat, both derived from progenitor cells named mesenchymal stem cells (MSCs). In addition, the pathogenic role of MSCs in other diseases sharing common properties with CS, such as an altered inflammatory profile and increased oxidative stress, has been identified. In this light, MSCs isolated from skin of control healthy subjects (C-MSCs), patients affected by endogenous CS (ENDO-MSCs), patients affected by iatrogenic CS (IATRO-MSCs) and patients affected by exogenous CS receiving steroid-sparing drugs (SS-MSCs), respectively, have been isolated and analyzed. ENDO- and IATRO-MSCs showed a reduced differentiative potential toward osteogenic and adipogenic lineages compared to C-MSCs, whereas SS-MSCs re-acquired the ability to differentiate, with a trend similar to control cells. In addition, MSCs from CS groups, compared to control MSCs, displayed a reduction in the secretion of cytokines (immune-suppression), a decreased expression of genes related to wound healing and a dysregulation of the enzymes/genes related to antioxidant capacity. In conclusion, our results suggest that the hallmarks of CS, such as wound healing impairment and immunosuppression, are already detectable in undifferentiated cells, which could be considered a potential therapeutic early target for control of CS.
库欣综合征（CS）由糖皮质激素（GCs）过量引起，与多种代谢性疾病的发生及伤口愈合受损密切相关。GCs水平过高的来源可用于区分内源性和外源性（医源性）CS。医源性患者通常还接受抗代谢药物治疗，这些药物是现代类固醇节省免疫抑制疗法的基础。CS主要靶向的组织是骨骼和脂肪，二者均来源于名为间充质干细胞（MSCs）的祖细胞。此外，已确定MSCs在其他与CS具有共同特征的疾病中发挥致病作用，如炎症特征改变和氧化应激增加。鉴于此，分别从健康对照受试者皮肤（C-MSCs）、内源性CS患者（ENDO-MSCs）、医源性CS患者（IATRO-MSCs）以及接受类固醇节省药物的外源性CS患者（SS-MSCs）中分离并分析了MSCs。与C-MSCs相比，ENDO-MSCs和IATRO-MSCs向成骨和成脂谱系的分化潜能降低，而SS-MSCs重新获得了分化能力，其趋势与对照细胞相似。此外，与对照MSCs相比，CS组的MSCs细胞因子分泌减少（免疫抑制），伤口愈合相关基因表达降低，抗氧化能力相关酶/基因失调。总之，我们的结果表明，CS的特征，如伤口愈合受损和免疫抑制，在未分化细胞中已经可以检测到，这些细胞可被视为控制CS的潜在早期治疗靶点。
