Metabolic Maturation in hiPSC-Derived Cardiomyocytes: Emerging Strategies for Inducing the Adult Cardiac Phenotype
Abstract
1. Introduction
2. Cardiac Metabolic Maturation
From Fetal to Adult Heart: Mitochondria and Metabolic Switch
3. Strategies to Induce Metabolic Maturation in hiPSC-Derived Cardiomyocytes
Maturation Technique | Effect | Reference |
---|---|---|
Long-term culture | After 100 days of culture, mitochondrial relative abundance, mitochondrial membrane potential, and activity of respiratory complexes I–III increased. | [34] |
200 days of culture result in metabolic maturation by promoting the shift from glycolysis to β-oxidation and activation of the cAMP-PKA-proteasome axis. | [35] | |
Stimulation with isoproterenol (100 nM) led to a greater increase in the extracellular acidification rate at day 45 than at day 37. | [36] | |
After 12 weeks of post-differentiation culture, hiPSC-CMs showed increased ability to oxidize fatty acids and reduced glucose oxidation. Structural and functional maturation of mitochondria. | [37] | |
Hormonal regulators | Triiodothyronine (T3) treatment for 1 week after differentiation induces an increase in respiratory reserve capacity. | [38] |
Treatment with triiodothyronine, insulin-like growth factor-1, and dexamethasone (TID) between days 16 and 21 of differentiation resulted in increased respiratory rate. | [39] | |
TID treatment increased expression of long-chain fatty acid transporter CD36, mitochondrial uncoupling protein UCP3, fatty acid synthase, GLUT4, and pyruvate dehydrogenase kinase 4. | [40] | |
Metabolic substrates | Lactate-containing medium induced higher GLUT4 membrane translocation after insulin stimulation. | [28] |
Cultivation for 3–5 weeks in a maturation medium containing a complex mixture of albumin-bound fatty acids induced a metabolic maturation with higher levels of fatty acid oxidation. | [11,41,42] | |
Maintenance medium for 20 days, composed of galactose, oleic acid, and palmitic acid, improves the oxidative capacity of hiPSC-CMs. | [43] | |
Incubation with lactate medium for the first 7 days after differentiation and a subsequent incubation for 3 to 7 days in glucose-free medium enriched with linoleic acid induced an adult-like metabolic profile. | [44] | |
Galactose rather than glucose in the medium improves metabolic maturation. | [45] | |
Functional maturation | Electrical conditioning to promote mitochondrial maturation and increase oxidative metabolism in engineered cardiac tissues does not show consistent maturation in sarcomere isoform expression. | [12] |
Electrostimulation promotes structural and electrophysiological maturation with benefits on action potential propagation and contraction synchronization, increased mitochondrial content, oxidative capacity, and more developed sarcomere structure. | [46] | |
Single-culture and multi-culture cardiac 3D models | Single-culture of 3D hiPSC-CMs shows downregulation of glycolytic genes and upregulation of mitochondrial oxidative phosphorylation genes matched by an increase in fatty acids oxidation and a reduction in glycolysis. | [47,48] |
Functional increase in oxidative metabolism but equal rates of glycolysis between undifferentiated and differentiated hiPSC-CMs spheroids. | [49] | |
3D multicellular cultures show elongated mitochondria and express genes involved in fatty acid β-oxidation. | [7,50] | |
3D multicellular cultures and crosstalk between cardiomyocytes, endothelial cells, and fibroblasts are essential for the metabolic maturation of hiPSC-CMs. | [7] | |
Engineered heart tissue (EHT) as a 3D model shows fatty acid oxidation activation and modulation with oleate. Stimulation of peroxisome proliferator-activated receptor alpha (PPARα) in 3D EHT further increased oxidative metabolism. | [51] | |
Long-term human organotypic cardiac microtissues (hOCMs), scaffold-free multicellular beating human cardiac microtissues, show elongated mitochondria, express genes involved in fatty acid β-oxidation, and rely more on mitochondrial respiration. | [50] |
3.1. Long-Term Culture
3.2. Hormonal Regulators
3.3. Metabolic Substrates
3.4. Functional Maturation
3.5. Single-Culture and Multi-Culture Cardiac 3D Models
4. HiPSC-CMs as a Tool for Disease Modeling and Drug Screening
4.1. Three-Dimensional Cultures to Model Metabolic Cardiac Diseases
4.2. HiPSC-CMs in Drug Screening Models
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ES | Embryonic Stem |
iPSCs | Inducible Pluripotent Stem Cells |
hiPSC-CMs | Human Inducible Pluripotent Stem Cell-derived cardiomyocyte |
T3 | Triiodothyronine |
CM | Cardiomyocyte |
ATP | Adenosine Triphosphate |
GLUT | Glucose Transporter |
FFAs | Free Fatty Acids |
cAMP-PKA | Cyclic Adenosine Monophosphate-Protein Kinase A |
pAKT | Phospho Protein Kinase B |
AS160 | Akt Substrate 160 |
IGF-1 | Insulin-like Growth Factor-1 |
TID | T3, IGF-1 and dexamethasone |
CD36 | Long Chain Fatty Acid Transporter |
FABPpm | Plasma Membrane isoform of Fatty Acid Binding Protein |
FATP | Fatty Acid Transport Protein |
UCP | Uncoupling Protein |
FASN | Fatty Acid Synthase |
PDK | Pyruvate Dehydrogenase Kinase |
hOCMs | Human Organotypic Cardiac Microtissues |
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Malan, D.; Gallo, M.P.; Geddo, F.; Levi, R.; Querio, G. Metabolic Maturation in hiPSC-Derived Cardiomyocytes: Emerging Strategies for Inducing the Adult Cardiac Phenotype. Pharmaceuticals 2025, 18, 1133. https://doi.org/10.3390/ph18081133
Malan D, Gallo MP, Geddo F, Levi R, Querio G. Metabolic Maturation in hiPSC-Derived Cardiomyocytes: Emerging Strategies for Inducing the Adult Cardiac Phenotype. Pharmaceuticals. 2025; 18(8):1133. https://doi.org/10.3390/ph18081133
Chicago/Turabian StyleMalan, Daniela, Maria Pia Gallo, Federica Geddo, Renzo Levi, and Giulia Querio. 2025. "Metabolic Maturation in hiPSC-Derived Cardiomyocytes: Emerging Strategies for Inducing the Adult Cardiac Phenotype" Pharmaceuticals 18, no. 8: 1133. https://doi.org/10.3390/ph18081133
APA StyleMalan, D., Gallo, M. P., Geddo, F., Levi, R., & Querio, G. (2025). Metabolic Maturation in hiPSC-Derived Cardiomyocytes: Emerging Strategies for Inducing the Adult Cardiac Phenotype. Pharmaceuticals, 18(8), 1133. https://doi.org/10.3390/ph18081133