PSME4 determines mesenchymal stem cell fate towards cardiac commitment through YAP1 degradation

Area of Science:

• Cardiovascular Research
• Stem Cell Biology
• Molecular Medicine

Background:

• Myocardium regeneration after injury is difficult.
• Mesenchymal stem cells (MSCs) are promising for cardiac repair but differentiate slowly.
• The role of PSME4 in MSC cardiac differentiation is unclear.

Purpose of the Study:

• To investigate the role of PSME4 in the cardiac commitment of MSCs.
• To elucidate the mechanism by which PSME4 influences MSC differentiation into cardiomyocytes.

Main Methods:

• Primary mouse MSCs and immortalized human MSCs were used.
• PSME4 knockout and knockdown models were created.
• Apicidin, shYAP1, tubastatin A, and HDAC6 siRNA were employed.
• Immunofluorescence and Western blot analyses were performed.

Main Results:

• Apicidin treatment rapidly induced cardiac commitment in mouse MSCs.
• PSME4 knockout/knockdown prevented apicidin-induced cardiac commitment.
• PSME4 knockdown led to YAP1 nuclear retention.
• Simultaneous YAP1 knockdown and apicidin treatment accelerated commitment.
• Acetylation-resistant YAP1 overexpression inhibited cardiac commitment.

Conclusions:

• PSME4 is essential for MSC cardiac commitment.
• HDAC inhibition leads to YAP1 acetylation and nuclear translocation.
• PSME4 degrades acetylated YAP1, promoting cardiomyocyte differentiation.
• YAP1 nuclear retention or failure of degradation blocks cardiac commitment.