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Cardiovascular Engineering

Cardiovascular Engineering - Poster Session C

Poster H10 - Enriched Fatty Acid Media Enhanced Contractile Functionality of hiPSC-laden hydrogel-derived Engineered Cardiac Tissue

Friday, October 25, 2024
10:00 AM - 11:00 AM EST
Location: Exhibit Hall E, F & G

Introduction:  Cardiovascular disease, a global leading cause of death, demands advanced functional engineered cardiac tissue models for accurate disease modeling, drug studies, and pre-clinical tests. A specific focus is on diabetic cardiomyopathy (DCM), a condition causing structural and functional abnormalities in diabetic hearts. Human-induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) present great potential for disease modeling. However, previous studies on two-dimensional (2D) substrates resulted in hiPSC-CMs with an immature phenotype, such as weak contractile forces and cell homogeneity. DCM is primarily found in adult patients, so it is critical to develop a model that accurately replicates mature contractile function and interaction with the extracellular matrix found in the adult human heart. Three-dimensional tissues address this need for more accurate models by recapitulating native tissue complexity.

Materials and

Methods:  Our prior work demonstrated hiPSCs in PEG-fibrinogen (PF) hydrogels successfully achieve cardiac differentiation and a more-mature phenotype compared to 2D differentiated cells. Here, we created engineered cardiac tissues (ECTs) by encapsulating hiPSCs in rectangular PF hydrogels followed by in situ cardiac differentiating. It has been reported that culturing ECTs in RPMI1/B27 medium supplemented with insulin (RP) primarily supported glucose oxidation as the main energy source. In contrast, native human heart tissue relies predominantly on fatty acid oxidation for energy production, with glucose oxidation contributing to only approximately 30% of ATP synthesis. To better simulate this physiological environment, we cultured ECTs in a fully defined metabolic maturation (MM) medium enriched with fatty acids, specifically oleic and palmitic acids, to promote fatty acid oxidation as the primary energy source. To study the impact of MM media on the contractile functionality and structural maturation of hiPSC-CMs, we compared them to age-matched RPMI/B27 with insulin (RP)-cultured samples. The contractile functionality of the tissues was evaluated using microscopy. Additionally, morphology and sarcomere structure were analyzed through staining of sarcomeres.

Results, Conclusions, and Discussions: ECTs in MM exhibited higher contraction frequency (1.4-fold), contraction and relaxation velocities (2.9 and 3.2-fold), and directionality (1.95-fold), along with significantly greater maximal fractional shortening (7.3-fold) on day 16 compared to RP (n≥3 individual batches with at least two tissues per batch). These data collectively suggest a significant improvement in contractile functionality in the ECTs cultured in MM. In conclusion, our study indicated that one week of ECT culture in enriched fatty acid media promoted the contractile functionality of hiPSC-CMs in ECTs. This strategy provides a more-appropriate, mature model for studying cardiac disease, especially for metabolic diseases like DCM.

Acknowledgements (Optional):