LRP6 downregulation promotes cardiomyocyte proliferation and heart regeneration

Area of Science:

• Cardiovascular Biology
• Regenerative Medicine
• Molecular Cardiology

Background:

• The adult mammalian heart has limited regenerative capacity due to postmitotic cardiomyocytes.
• Low-density lipoprotein receptor-related protein 6 (LRP6), a Wnt co-receptor, is crucial for embryonic heart development.

Purpose of the Study:

• To investigate the role of LRP6 in regulating cardiomyocyte proliferation and cardiac repair.
• To explore LRP6 as a potential therapeutic target for myocardial regeneration.

Main Methods:

• Utilized Lrp6 deficiency models in neonatal, juvenile, and adult mice, including cardiomyocyte-specific deletion.
• Performed myocardial infarction (MI) induction and assessed cardiac function and regeneration.
• Employed in vivo genetic lineage tracing and gene therapy with adeno-associated virus (AAV)9 miRNAi-Lrp6.
• Investigated the proliferation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).

Main Results:

• Lrp6 deficiency significantly increased cardiomyocyte cell cycle activity across all age groups.
• Cardiomyocyte-specific Lrp6 deletion promoted robust cardiac regeneration post-MI, reducing infarct size and improving left ventricular function.
• Newly formed cardiomyocytes originated from resident cardiomyocytes, and the pro-proliferative effect was linked to the ING5/P21 pathway.
• AAV9-mediated Lrp6 knockdown facilitated heart injury repair in mice and enhanced iPSC-CM proliferation.

Conclusions:

• LRP6 is identified as a critical negative regulator of cardiomyocyte proliferation in the adult heart.
• Targeting LRP6 presents a promising molecular strategy for promoting myocardial regeneration and cardiac repair.
• This research opens avenues for novel therapeutic interventions for heart disease.