2. Academic Validation
  3. Mesenchymal stem cells exosomal let-7a-5p improve autophagic flux and alleviate liver injury in acute-on-chronic liver failure by promoting nuclear expression of TFEB

Mesenchymal stem cells exosomal let-7a-5p improve autophagic flux and alleviate liver injury in acute-on-chronic liver failure by promoting nuclear expression of TFEB

  • Cell Death Dis. 2022 Oct 12;13(10):865. doi: 10.1038/s41419-022-05303-9.
Dengna Lin # 1 2,  Hao Chen # 3,  Jing Xiong # 1 2,  Jing Zhang 1 2,  Zhaoxia Hu 1 2,  Juan Gao 1 2,  Bin Gao 1,  Shaoquan Zhang 1,  Junfeng Chen 1,  Huijuan Cao 1,  Zhihui Li 1 2,  Bingliang Lin 4 5 6,  Zhiliang Gao 7 8
Affiliations

Affiliations

  • 1 Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
  • 2 Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
  • 3 Department of Neurology, the First Affiliated Hospital of Nanchang University, Nanchang, China.
  • 4 Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. linbingl@mail.sysu.edu.cn.
  • 5 Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. linbingl@mail.sysu.edu.cn.
  • 6 Key Laboratory of Tropical Disease Control, Sun Yat-Sen University, Ministry of Education, Guangzhou, China. linbingl@mail.sysu.edu.cn.
  • 7 Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. gaozhl@mail.sysu.edu.cn.
  • 8 Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. gaozhl@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 36224178 DOI: 10.1038/s41419-022-05303-9
Abstract

Acute-on-chronic liver failure is a distinct clinical syndrome characterized by a dysregulated immune response and extensive hepatocyte death without satisfactory therapies. As a cytoplasmic degradative and quality-control process, Autophagy was implicated in maintaining intracellular homeostasis, and decreased hepatic Autophagy was found in many liver diseases and contributes to disease pathogenesis. Previously, we identified the therapeutic potential of mesenchymal stem cells (MSCs) in ACLF patients; however, the intrinsic mechanisms are incompletely understood. Herein, we showed that MSCs restored the impaired autophagic flux and alleviated liver injuries in ACLF mice, but these effects were abolished when autophago-lysosomal maturation was inhibited by leupeptin (leu), suggesting that MSCs exerted their hepatoprotective function in a pro-autophagic dependent manner. Moreover, we described a connection between transcription factor EB (TFEB) and autophagic activity in this context, as evidenced by increased nuclei translocation of TFEB elicited by MSCs were capable of promoting liver Autophagy. Mechanistically, we confirmed that let-7a-5p enriched in MSCs derived exosomes (MSC-Exo) could activate Autophagy by targeting MAP4K3 to reduce TFEB phosphorylation, and MAP4K3 knockdown partially attenuates the effect of anti-let-7a-5p oligonucleotide via decreasing the inflammatory response, in addition, inducing Autophagy. Altogether, these findings revealed that the hepatoprotective effect of MSCs may partially profit from its exosomal let-7a-5p mediating Autophagy repairment, which may provide new insights for the therapeutic target of ACLF treatment.

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