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Advances in maturation of human induced pluripotent stem cell-derived cardiomyocytes and 3D engineered cardiac tissue.

Commented by the ESC WG on Cardiovascular Regenerative & Reparative Medicine

History of Cardiology
Gene Therapy, Cell Therapy
Basic Science
Clinical Skills

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are key tools in cardiac regenerative medicine. They can be used to model disease, test new therapies, or create engineered cardiac tissue to replace damaged myocardium. However, current iPSC-CMs are functionally immature, resembling fetal or neonatal cardiomyocytes. The main challenges in accurately modeling the physiological behavior of adult cardiomyocytes, include achieving the proper formation of sarcomeres, stable gap junctions, adult-like electrophysiological properties and ion channels. To address them, researchers are developing appropriate culture conditions that can promote the maturation of iPSC-CMs. 

The highlighted article from Chirico et al (1) proposed an economical method to induce iPSC-CM maturation via the activation of the peroxisome proliferator-activated receptor β/δ and gamma coactivator 1-alpha (PPAR/PGC-1α) pathway in a fatty acid-supplemented medium using asiatic acid (AA) and GW501516 (GW). After 10 days of treatment, iPSC-CM maturation was evaluated using a multiparametric quality assessment, showing increased expression of FA metabolism-related genes and markers for mitochondrial activity, increased substrate utilization, improved structural maturity, and increased ion channel gene expression and protein levels. 
Additionally, the other selected article by Callaghan et al (2) used an elegant differential approach to develop an optimized iPSC-CM maturation medium formulation. This medium improved the morphology, calcium handling, electrophysiology, and metabolism. 

Creating a 3D structure of native heart tissue is a current challenge for cardiac tissue engineering, which is addressed in the two other selected articles. Mohammadi et al (3) described a method relying on microfabricated elastomers to control cell orientation and contact. The hierarchical assembly of the 2D aligned cell sheets resulted in a functional 3D conical cardiac ventricle. Finally, Kalhori et al (4) reviewed the current challenges and perspectives in bioprinting, including bioinks, cells, hydrogels, biofactors, bioprinting techniques, and biophysical stimulations.


(1) Chirico N et al. Small molecule-mediated rapid maturation of human induced pluripotent stem cell-derived cardiomyocytes. Stem Cell Res Ther. 2022 Dec 27;13(1):531. doi: 10.1186/s13287-022-03209-z. 

(2) Callaghan NI, Advanced physiological maturation of iPSC-derived human cardiomyocytes using an algorithm-directed optimization of defined media components. bioRxiv. 2022 preprint

(3)Mohammadi MH, et al. Toward Hierarchical Assembly of Aligned Cell Sheets into a Conical Cardiac Ventricle Using Microfabricated Elastomers. Adv Biol (Weinh). 2022 Nov;6(11):e2101165. doi: 10.1002/adbi.202101165. 

(4) Kalhori D et al. Cardiovascular 3D bioprinting: A review on cardiac tissue development. Bioprinting. 2022 28 :e00221. 10.1016/j.bprint.2022.e00221

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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