Universität zu Köln

Chirico, Nino, Kessler, Elise L., Maas, Renee G. C., Fang, Juntao, Qin, Jiabin, Dokter, Inge, Daniels, Mark, Saric, Tomo, Neef, Klaus, Buikema, Jan-Willem, Lei, Zhiyong, Doevendans, Pieter A., Sluijter, Joost P. G. and van Mil, Alain (2022). Small molecule-mediated rapid maturation of human induced pluripotent stem cell-derived cardiomyocytes. Stem Cell Res. Ther., 13 (1). LONDON: BMC. ISSN 1757-6512

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Abstract

Background: Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) do not display all hallmarks of mature primary cardiomyocytes, especially the ability to use fatty acids (FA) as an energy source, containing high mitochondrial mass, presenting binucleation and increased DNA content per nuclei (polyploidism), and synchronized electrical conduction. This immaturity represents a bottleneck to their application in (1) disease modelling-as most cardiac (genetic) diseases have a middle-age onset-and (2) clinically relevant models, where integration and functional coupling are key. So far, several methods have been reported to enhance iPSC-CM maturation; however, these protocols are laborious, costly, and not easily scalable. Therefore, we developed a simple, low-cost, and rapid protocol to promote cardiomyocyte maturation using two small molecule activators of the peroxisome proliferator-activated receptor beta/delta and gamma coactivator 1-alpha (PPAR/PGC-1 alpha) pathway: asiatic acid (AA) and GW501516 (GW). Methods and Results: Monolayers of iPSC-CMs were incubated with AA or GW every other day for ten days resulting in increased expression of FA metabolism-related genes and markers for mitochondrial activity. AA-treated iPSC-CMs responsiveness to the mitochondrial respiratory chain inhibitors increased and exhibited higher flexibility in substrate utilization. Additionally, structural maturity improved after treatment as demonstrated by an increase in mRNA expression of sarcomeric-related genes and higher nuclear polyploidy in AA-treated samples. Furthermore, treatment led to increased ion channel gene expression and protein levels. Conclusions: Collectively, we developed a fast, easy, and economical method to induce iPSC-CMs maturation via PPAR/PGC-1 alpha activation. Treatment with AA or GW led to increased metabolic, structural, functional, and electrophysiological maturation, evaluated using a multiparametric quality assessment.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Chirico, Nino UNSPECIFIED UNSPECIFIED UNSPECIFIED Kessler, Elise L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Maas, Renee G. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fang, Juntao UNSPECIFIED UNSPECIFIED UNSPECIFIED Qin, Jiabin UNSPECIFIED UNSPECIFIED UNSPECIFIED Dokter, Inge UNSPECIFIED UNSPECIFIED UNSPECIFIED Daniels, Mark UNSPECIFIED UNSPECIFIED UNSPECIFIED Saric, Tomo UNSPECIFIED UNSPECIFIED UNSPECIFIED Neef, Klaus UNSPECIFIED UNSPECIFIED UNSPECIFIED Buikema, Jan-Willem UNSPECIFIED UNSPECIFIED UNSPECIFIED Lei, Zhiyong UNSPECIFIED UNSPECIFIED UNSPECIFIED Doevendans, Pieter A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sluijter, Joost P. G. UNSPECIFIED UNSPECIFIED UNSPECIFIED van Mil, Alain UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-683685
DOI:	10.1186/s13287-022-03209-z
Journal or Publication Title:	Stem Cell Res. Ther.
Volume:	13
Number:	1
Date:	2022
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1757-6512
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language FATTY-ACID OXIDATION; RIGHT-VENTRICULAR DYSPLASIA; L-THYRONINE PROMOTES; ASIATIC ACID; SKELETAL-MUSCLE; MITOCHONDRIAL BIOGENESIS; PENTACYCLIC TRITERPENE; CENTELLA-ASIATICA; PPAR-BETA/DELTA; HEART Multiple languages Cell & Tissue Engineering; Cell Biology; Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68368