Cardiomyocyte differentiation from human induced pluripotent stem cells is delayed following knockout of Bcl-2

Area of Science:

• Cardiovascular Biology
• Stem Cell Biology
• Molecular Biology

Background:

• The anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) is known for regulating cell death, survival, and autophagy.
• Its specific role in cardiomyocyte differentiation is less understood, necessitating further investigation into its mechanisms.

Purpose of the Study:

• To investigate the role of Bcl-2 in cardiomyocyte differentiation.
• To elucidate the mechanisms by which Bcl-2 influences cardiac development using human induced pluripotent stem cells (hiPSCs).

Main Methods:

• CRISPR/Cas9 gene editing was employed to create a BCL2 knockout (KO) in hiPSCs.
• The study analyzed the consequences of BCL2 KO on the differentiation of hiPSCs into cardiomyocytes.

Main Results:

• BCL2 KO resulted in a delayed differentiation of hiPSCs into cardiomyocytes.
• This delay was not attributed to the canonical anti-apoptotic function of Bcl-2.
• Reduced expression and activity of the cardiomyocyte Ca2+ toolkit were observed.
• BCL2 KO led to decreased c-Myc expression and nuclear localization during early cardiac differentiation.

Conclusions:

• Bcl-2 plays a significant role in the differentiation and maturation of cardiomyocytes.
• The observed delay in cardiac differentiation is partly mediated by reduced c-Myc expression and altered Ca2+ handling.
• These findings highlight a novel function of Bcl-2 beyond its anti-apoptotic role in cardiac development.