不同的MYC酸化驱动了对压力的不同胆管细胞反应
Steven P O'Hara1, Patrick L Splinter1, Antonia Felzen1
1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
概括
在原发性硬化性胆道炎 (PSC) 中,MYC蛋白充当分子开关,指导胆道细胞向增殖或衰老. 准MYC和GSK3B为PSC提供了潜在的治疗策略.
科学领域:
- 肝病学 肝病学是一种肝病学.
- 细胞生物学 细胞生物学
- 分子机制的分子机制
背景情况:
- 原发性硬化性胆管炎 (PSC) 涉及不同的胆管细胞反应:细胞循环停止 (衰老) 和增殖 (状反应).
- 了解驱动这些独特的胆细胞命运的机制对于PSC病变产生至关重要.
研究的目的:
- 为了研究基底的分子机制胆细胞衰老和PSC的增殖.
- 为了确定关键的调节者,如MYC和GSK3B,这些调节者控制胆细胞命运,以应对细胞压力.
主要方法:
- 分析人类PSC和控制肝脏组织使用免疫光检测衰老和增殖胆管细胞.
- 在体外研究中,使用正常的人类胆细胞 (NHC) 与LPS进行压力,采用FACS排序的衰老和耐药分数.
- RNA测序,qPCR和免疫血栓测试以评估MYC,GSK3B和衰老标志物.
- 在实验室和体内,对MYC和GSK3B的抑制和基因操纵,对PSC的小鼠模型.
主要成果:
- 与对照人群相比,PSC肝脏组织表现出老化和增殖胆血管细胞的增加.
- 富含MYC响应基因的衰老耐药胆血管细胞显示出增多的增殖标志物和改变的MYC酸化.
- 抑制MYC促进了衰老,而它的突变减少了衰老并增强了增殖.
- 在衰老的胆血管细胞中,GSK3B的抑制或耗尽减少了MYC酸化和衰老.
- 在PSC小鼠模型中,MYC抑制降低了胆血管细胞增殖和纤维化,而GSK3B抑制增加了它们.
结论:
- MYC酸化起到关键分子开关的作用,决定胆细胞是否发生增殖或衰老.
- 包括GSK3B在内的酶介质在调节胆管细胞命运方面发挥着重要作用.
- MYC被确定为PSC中胆管细胞行为的应激反应调节器.
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