Kim Yu-Hee, Jeong Seonghee, Cho Kyung-Ah, Woo So-Youn, Han Seung-Ho, Ryu Kyung-Ha
Advance Biomedical Research Institute, Ewha Womans University Seoul Hospital, Seoul, South Korea.
Ewha Medical Academy, Ewha Womans University Medical Center, Seoul, South Korea.
Tissue Eng Regen Med. 2025 Feb;22(2):237-248. doi: 10.1007/s13770-024-00697-3. Epub 2025 Jan 28.
Exogenous Cushing's syndrome, which results from prolonged glucocorticoid treatment, is associated with metabolic abnormalities. Previously, we reported the inhibitory effect of tonsil-derived mesenchymal stem cell conditioned medium (T-MSC CM) on glucocorticoid signal transduction. In this study, we investigated the therapeutic efficacy of T-MSCs in a mouse model of exogenous Cushing's syndrome.
Exogenous Cushing's syndrome model mice was generated by corticosterone administration in the drinking water for 5 weeks, and T-MSCs were injected intraperitoneally twice during the third week. Serum lipid profiles were measured using a chemistry analyzer. HepG2 cells were treated with dexamethasone and co-cultured with T-MSCs. Expression levels of genes involved in cholesterol metabolism were examined using real-time PCR. Low-density lipoprotein receptor (LDLR) protein levels were determined using western blotting and immunohistochemistry. Liver RNA extracted from the CORT and CORT + MSC mouse groups was used for transcriptome sequencing analysis and protein-protein interaction analysis.
Weight reduction and improvements in dyslipidemia by T-MSC administration were observed only in female mice. T-MSCs reduce circulating LDL cholesterol levels by downregulating liver X receptor α (LXRα) and inducible degrader of LDLR (IDOL) expression, thereby stabilizing LDLRs in the liver. Transcriptome analysis of liver tissue revealed pathways that are regulated by T-MSCs administration.
Administration of MSCs to female mice receiving chronic corticosterone treatment reduced the circulating LDL cholesterol level by downregulating the LXRα-IDOL axis in hepatocytes. These results suggest that T-MSCs may offer a novel therapeutic strategy for managing exogenous Cushing's syndrome by regulating cholesterol metabolism.
外源性库欣综合征由长期糖皮质激素治疗引起，与代谢异常有关。此前，我们报道了扁桃体来源的间充质干细胞条件培养基（T-MSC CM）对糖皮质激素信号转导的抑制作用。在本研究中，我们调查了T-MSCs在外源性库欣综合征小鼠模型中的治疗效果。
通过在饮用水中给予皮质酮5周建立外源性库欣综合征模型小鼠，并在第三周腹腔注射T-MSCs两次。使用化学分析仪测量血清脂质谱。用地塞米松处理HepG2细胞并与T-MSCs共培养。使用实时PCR检测参与胆固醇代谢的基因的表达水平。使用蛋白质印迹和免疫组织化学测定低密度脂蛋白受体（LDLR）蛋白水平。从CORT和CORT + MSC小鼠组提取的肝脏RNA用于转录组测序分析和蛋白质-蛋白质相互作用分析。
仅在雌性小鼠中观察到给予T-MSCs后体重减轻和血脂异常改善。T-MSCs通过下调肝脏X受体α（LXRα）和LDLR诱导降解物（IDOL）的表达来降低循环LDL胆固醇水平，从而稳定肝脏中的LDLR。肝脏组织的转录组分析揭示了受T-MSCs给药调节的途径。
对接受慢性皮质酮治疗的雌性小鼠给予MSCs可通过下调肝细胞中的LXRα-IDOL轴来降低循环LDL胆固醇水平。这些结果表明，T-MSCs可能通过调节胆固醇代谢为管理外源性库欣综合征提供一种新的治疗策略。
