Regulation of heart regeneration by LSD1 through suppressing CEND1

Area of Science:

• Cardiovascular Biology
• Epigenetics
• Regenerative Medicine

Background:

• Reactivating cardiomyocyte proliferation is key for heart regeneration.
• The LSD1-CEND1 axis epigenetically represses Cend1, which is essential for cardiomyocyte proliferation and heart development.

Purpose of the Study:

• To investigate the role of the LSD1-CEND1 axis in heart regeneration and repair after injury.
• To explore therapeutic strategies for enhancing cardiac repair.

Main Methods:

• Used cardiomyocyte-specific Lsd1 knockout/overexpression and Cend1 null/overexpression mouse models.
• Induced cardiac injury via apical resection (neonatal) or coronary artery ligation (adult).
• Assessed cardiac function (echocardiography) and histology (Masson staining); analyzed molecular changes (RNA-seq, qPCR, Western blot, immunostaining).

Main Results:

• Lsd1 deletion impaired neonatal heart regeneration; Lsd1 overexpression improved it.
• Cend1, a suppressor of cardiomyocyte cycling, was upregulated upon Lsd1 loss.
• Cend1 overexpression hindered regeneration; Cend1 deletion promoted it, enhancing cardiomyocyte proliferation, neovascularization, and macrophage activation.
• Lsd1 loss-induced regeneration defects were rescued by Cend1 deletion.
• Lsd1 overexpression or Cend1 deletion improved cardiac function post-myocardial infarction in adult mice.

Conclusions:

• LSD1-dependent suppression of CEND1 is critical for heart regeneration in neonatal and adult mice.
• Targeting LSD1 activation and CEND1 inhibition may offer therapeutic strategies for endogenous cardiac repair.