Metabolically driven maturation of human-induced-pluripotent-stem-cell-derived cardiac microtissues on microfluidic...

Area of Science:

• Cardiovascular Biology
• Stem Cell Biology
• Biomedical Engineering

Background:

• Immature human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have limited use in drug screening and disease modeling.
• Maturation is crucial for hiPSC-CMs to accurately mimic adult human cardiac physiology.

Purpose of the Study:

• To investigate methods for enhancing the maturation of hiPSC-CMs.
• To assess the impact of maturation on hiPSC-CM electrophysiology and calcium handling.
• To improve the utility of hiPSC-CMs for modeling cardiac diseases and drug responses.

Main Methods:

• Utilized microfluidic chips to enhance alignment and extracellular-matrix production of hiPSC-CM cardiac microtissues.
• Applied combinations of mechanical stimuli and metabolic cues, including fatty-acid-enriched media, to promote cardiomyocyte maturation.
• Assessed action-potential morphology, calcium handling, mitochondrial structure, and spontaneous beat rate.

Main Results:

• Fatty-acid-enriched media improved mitochondrial structure and calcium handling in hiPSC-CMs.
• Maturation cues led to cell-source-dependent, yet converging, effects on action-potential duration (APD), normalizing prolonged or shortened APDs.
• Tissue maturation reduced variability in beat rate and APD, aligning phenotypes with adult human ventricular cardiomyocytes.

Conclusions:

• Mechanical and metabolic cues effectively mature hiPSC-CMs, enhancing their physiological relevance.
• Mature hiPSC-CMs provide a more reliable model for studying cardiac electrophysiology and drug effects.
• This approach improves the modeling of pro-arrhythmic drug effects on cardiac tissue, advancing cardiovascular research.