Integrins Increase Sarcoplasmic Reticulum Activity for Excitation-Contraction Coupling in Human Stem Cell-Derived...

Area of Science:

• Cardiovascular Biology
• Cellular Physiology
• Biomaterials Science

Background:

• Cardiac excitation-contraction (EC)-coupling relies on sarcoplasmic reticulum (SR) Ca2+ store engagement.
• Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exhibit impaired SR Ca2+ utilization, mimicking disease states like heart failure.
• The extracellular matrix (ECM) is implicated in modulating cardiomyocyte function and EC-coupling.

Purpose of the Study:

• To investigate the role of integrin-ligand interactions between ECM proteins and cardiomyocytes in modulating EC-coupling.
• To test the hypothesis that ECM components recruit the SR for Ca2+ cycling during EC-coupling.
• To assess the functional and structural effects of specific ECM-derived peptides on hiPSC-CMs.

Main Methods:

• hiPSC-CMs cultured on fibronectin-coated surfaces and treated with arginine-glycine-aspartic acid (RGD) peptides.
• Caffeine-induced Ca2+ release assays to evaluate SR Ca2+ content and removal.
• Microelectrode recordings to analyze action potential duration.
• Confocal microscopy to assess co-localization of key proteins involved in EC-coupling.

Main Results:

• RGD peptides shortened hiPSC-CM Ca2+ transient and action potential duration.
• Treatment increased co-localization of L-type Ca2+ channels and ryanodine receptors.
• Enhanced rate of SR-mediated Ca2+ cycling was observed.

Conclusions:

• Integrin-binding peptides promote SR recruitment for Ca2+ cycling in EC-coupling.
• These peptides induce functional and structural improvements in hiPSC-CMs.
• The study underscores the critical role of the ECM in regulating cardiomyocyte physiology.