Zhang Jiebin, Lu Tongyu, Xiao Jiaqi, Du Cong, Chen Haitian, Li Rong, Sui Xin, Pan Zihao, Xiao Cuicui, Zhao Xuegang, Yao Jia, Liu Yasong, Lei Yunguo, Ruan Ying, Zhang Jian, Li Hua, Zhang Qi, Zhang Yingcai, Cai Jianye, Yang Yang, Zheng Jun
Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine. Guangzhou 510630, China; Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
Biological Treatment Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
J Control Release. 2023 Apr;356:402-415. doi: 10.1016/j.jconrel.2023.02.032. Epub 2023 Mar 11.
Aging is one of the critical factors to impair liver regeneration leading to a high incidence of severe complications after hepatic surgery in the elderly population without any effective treatment for clinical administration. As cell-free nanotherapeutics, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been demonstrated the therapeutic potentials on liver diseases. However, the effects of MSC-EVs on the proliferation of aged hepatocytes are largely unclear. In this study, we found MSCs could reduce the expression of senescence-associated markers in the liver and stimulate its regeneration in aged mice after receiving a two-thirds partial hepatectomy (PHx) through their secreted MSC-EVs. Using RNA-Seq and AAV9 vector, we mechanistically found that these effects of UC-MSC-EVs partially attributed to inducing Atg4B-related mitophagy. This effect repairs the mitochondrial status and functions of aged hepatocytes to promote their proliferation. And protein mass spectrum analysis uncovered that DEAD-Box Helicase 5 (DDX5) enriches in UC-MSC-EVs, which interacts with E2F1 to facilitate its nuclear translocation for activating the expression of Atg4B. Collectively, our data show that MSC-EVs act nanotherapeutic potentials in anti-senescence and promoting regeneration of aged liver by transferring DDX5 to regulate E2F1-Atg4B signaling pathway that induce mitophagy, which highlights the clinical application valuation of MSC-EVs for preventing severe complications in aged population receiving liver surgery.
衰老作为损害肝脏再生的关键因素之一，导致老年人群肝脏手术后严重并发症的发生率很高，临床上尚无有效的治疗方法。作为无细胞纳米疗法，间充质干细胞衍生的细胞外囊泡（MSC-EVs）已被证明对肝脏疾病具有治疗潜力。然而，MSC-EVs对衰老肝细胞增殖的影响在很大程度上尚不清楚。在本研究中，我们发现间充质干细胞（MSCs）可以通过其分泌的MSC-EVs降低衰老小鼠肝脏中衰老相关标志物的表达，并在接受三分之二部分肝切除术（PHx）后刺激其肝脏再生。通过RNA测序和腺相关病毒9（AAV9）载体，我们从机制上发现，脐带间充质干细胞来源的细胞外囊泡（UC-MSC-EVs）的这些作用部分归因于诱导自噬相关蛋白4B（Atg4B）相关的线粒体自噬。这种作用修复了衰老肝细胞的线粒体状态和功能，以促进其增殖。蛋白质质谱分析发现，解旋酶5（DDX5）在UC-MSC-EVs中富集，它与E2F1相互作用，促进其核转位，从而激活Atg4B的表达。总的来说，我们的数据表明，MSC-EVs通过传递DDX5来调节E2F1-Atg4B信号通路以诱导线粒体自噬，从而在抗衰老和促进衰老肝脏再生方面发挥纳米治疗潜力，这突出了MSC-EVs在预防接受肝脏手术的老年人群严重并发症方面的临床应用价值。
