Functional properties of human embryonic stem cell-derived cardiomyocytes

Area of Science:

• Cardiology
• Stem Cell Biology
• Regenerative Medicine

Background:

• Cardiac cell transplantation offers a promising approach for myocardial regeneration.
• Functional integration of transplanted cardiomyocytes with host myocardium is crucial for therapeutic efficacy.
• Understanding the properties of human embryonic stem cell-derived cardiomyocytes (hESC-CM) is essential for their clinical application.

Purpose of the Study:

• To investigate the excitation-contraction (E-C) coupling mechanisms in hESC-CM.
• To assess the responsiveness of hESC-CM to physiological stimuli.
• To compare the functional properties of hESC-CM with mature myocardium.

Main Methods:

• Utilized fura-2 fluorescence to measure intracellular calcium ([Ca(2+)](i)) transients.
• Employed video edge detection to quantify cardiomyocyte contractions.
• Administered electrical pacing, varied extracellular calcium ([Ca(2+)](o)), and used pharmacological agents like verapamil, ryanodine, thapsigargin, and caffeine.

Main Results:

• hESC-CM responded to electrical pacing with corresponding [Ca(2+)](i) transients and contractions.
• hESC-CM exhibited negative force-frequency relationships, differing from adult myocardium.
• Contraction was dependent on [Ca(2+)](o) and inhibited by verapamil, but unaffected by ryanodine, thapsigargin, or caffeine.
• These findings indicate contraction is primarily driven by extracellular calcium, not sarcoplasmic reticulum stores, in 45-60 day old hESC-CM.

Conclusions:

• hESC-CM at 45-60 days developmental stage display immature excitation-contraction coupling.
• The sarcoplasmic reticulum function appears underdeveloped, leading to a reliance on extracellular calcium for contraction.
• Genetic modification of hESC-CM may be necessary to align their properties with adult myocardium for effective cardiac regeneration.