Retinoic acid modulation guides human-induced pluripotent stem cell differentiation towards left or right ventricle-like cardiomyocytes

Hengliang Zhang, Payel Sen, Jules Hamers, Theresa Sittig, Brent Woestenburg, Allessandra Moretti, Andreas Dendorfer, Daphne Merkus*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background:
Cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) by traditional methods are a mix of atrial and ventricular CMs and many other non-cardiomyocyte cells. Retinoic acid (RA) plays an important role in regulation of the spatiotemporal development of the embryonic heart.

Methods:
CMs were derived from hiPSC (hi-PCS-CM) using different concentrations of RA (Control without RA, LRA with 0.05μM and HRA with 0.1 μM) between day 3-6 of the differentiation process. Engineered heart tissues (EHTs) were generated by assembling hiPSC-CM at high cell density in a low collagen hydrogel.

Results:
In the HRA group, hiPSC-CMs exhibited highest expression of contractile proteins MYH6, MYH7 and cTnT. The expression of TBX5, NKX2.5 and CORIN, which are marker genes for left ventricular CMs, was also the highest in the HRA group. In terms of EHT, the HRA group displayed the highest contraction force, the lowest beating frequency, and the highest sensitivity to hypoxia and isoprenaline, which means it was functionally more similar to the left ventricle. RNAsequencing revealed that the heightened contractility of EHT within the HRA group can be attributed to the promotion of augmented extracellular matrix strength by RA.

Conclusion:
By interfering with the differentiation process of hiPSC with a specific concentration of RA at a specific time, we were able to successfully induce CMs and EHTs with a phenotype similar to that of the left ventricle or right ventricle.

Original languageEnglish
Article number184
Number of pages18
JournalStem Cell Research and Therapy
Volume15
Issue number1
Early online date21 Jun 2024
DOIs
Publication statusE-pub ahead of print - 21 Jun 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

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