The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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PSME4 determines mesenchymal stem cell fate towards cardiac commitment through YAP1 degradation

  • Mira Kim (Department of Pharmacology, Chonnam National University Medical School) ;
  • Yong Sook Kim (Biomedical Research Institute) ;
  • Youngkeun Ahn (Department of Cardiology, Chonnam National University Hospital) ;
  • Gwang Hyeon Eom (Department of Pharmacology, Chonnam National University Medical School) ;
  • Somy Yoon (College of Pharmacy, Chonnam National University)
  • Received : 2023.04.12
  • Accepted : 2023.05.01
  • Published : 2023.07.01
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Abstract

The regeneration of myocardium following acute circulatory events remains a challenge, despite numerous efforts. Mesenchymal stem cells (MSCs) present a promising cell therapy option, but their differentiation into cardiomyocytes is a time-consuming process. Although it has been demonstrated that PSME4 degrades acetyl-YAP1, the role of PSME4 in the cardiac commitment of MSCs has not been fully elucidated. Here we reported the novel role of PSME4 in MSCs cardiac commitment. It was found that overnight treatment with apicidin in primary-cultured mouse MSCs led to rapid cardiac commitment, while MSCs from PSME4 knock-out mice did not undergo this process. Cardiac commitment was also observed using lentivirus-mediated PSME4 knockdown in immortalized human MSCs. Immunofluorescence and Western blot experiments revealed that YAP1 persisted in the nucleus of PSME4 knockdown cells even after apicidin treatment. To investigate the importance of YAP1 removal, MSCs were treated with shYAP1 and apicidin simultaneously. This combined treatment resulted in rapid YAP1 elimination and accelerated cardiac commitment. However, overexpression of acetylation-resistant YAP1 in apicidin-treated MSCs impeded cardiac commitment. In addition to apicidin, the universal effect of histone deacetylase (HDAC) inhibition on cardiac commitment was confirmed using tubastatin A and HDAC6 siRNA. Collectively, this study demonstrates that PSME4 is crucial for promoting the cardiac commitment of MSCs. HDAC inhibition acetylates YAP1 and facilitates its translocation to the nucleus, where it is removed by PSME4, promoting cardiac commitment. The failure of YAP1 to translocate or be eliminated from the nucleus results in the MSCs' inability to undergo cardiac commitment.

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Acknowledgement

We gratefully acknowledge the assistance of GPT-4.0, a large language model developed by OpenAI, for its help in grammar checking and refining our manuscript. It is important to note that GPT-4.0 was solely utilized for enhancing the grammatical quality of the text, and no new content was generated by the model. All intellectual contributions remain exclusively with the authors.

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