IGFBP2 Mediates Human iPSC-Cardiomyocyte Proliferation in a Cellular Contact-Dependent Manner

Area of Science:

• Cardiovascular Biology
• Stem Cell Biology
• Regenerative Medicine

Background:

• Cardiomyocyte proliferation is crucial for myocardial regeneration after injury.
• Intrinsic inhibitory mechanisms in cardiomyocytes limit their expansion.
• Cell-cell contact is hypothesized as a key suppressor of cardiomyocyte proliferation.

Purpose of the Study:

• To investigate the role of cell-cell contact in suppressing cardiomyocyte proliferation.
• To identify molecular pathways involved in this suppression.
• To enable sustained cardiomyocyte proliferation in 3D contexts.

Main Methods:

• Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured at varying densities.
• Phosphoproteomic profiling was used to identify signaling alterations.
• Conditioned media were analyzed for secreted growth factors.

Main Results:

• hiPSC-CM proliferation decreased with increased cell-cell contact, linked to adherens junction and sarcomere assembly.
• Cell contact reduced beta-catenin nuclear translocation and TCF/LEF activity.
• IGFBP2 enrichment in sparse cultures was identified as a pro-proliferative factor.

Conclusions:

• Cell-cell contact inhibits hiPSC-CM proliferation via adherens junctions, sarcomeric assembly, and reduced IGFBP2 secretion.
• Exogenous IGFBP2 can overcome contact inhibition, promoting 3D cardiac tissue growth.
• Findings advance cardiac tissue engineering and regenerative therapies.