High-throughput screening reveals multiple facets of hiPSC-CM maturation

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are an effective tool for drug screening and modeling patient-specific diseases in a laboratory setting. They offer a sustainable alternative to primary human cardiomyocytes, bypassing the ethical and supply issues associated with these cells. However, a major limitation is that hiPSC-CMs often exhibit immature characteristics that resemble fetal rather than adult heart cells. This immaturity impacts their structural, electrical, mechanical, and metabolic properties, limiting their effectiveness in accurately modeling adult heart diseases and testing drugs.

To address this, various strategies have been employed to enhance hiPSC-CM maturation, including extending culture periods, utilizing engineered surfaces that mimic heart stiffness, and applying mechanical and electrical stimulations. While promising, these methods are slow, labor-intensive, and not suited for high-throughput applications.

An alternative approach focuses on modifying the composition of the cell culture medium. This method leverages biochemical cues to induce maturation, offering a potentially scalable and efficient solution. However, most studies have used complex medium mixes with little understanding of how individual components contribute to the maturation process.

A recent study addresses these issues directly. Using high-throughput assays, including calcium imaging, impedance recordings (CardioExcyte96), and automated patch-clamp (SyncroPatch 384), the study dissects the roles of various medium components and their contributions to cell maturation. These high-throughput tools allowed the researchers to efficiently screen multiple medium formulations and their effects on the cells, significantly speeding up the optimization process.

Interestingly, the research demonstrates that functional, metabolic, and transcriptional maturation can occur independently in hiPSC-CMs. Researchers tested various medium formulations and identified which components are essential, beneficial, or unnecessary for promoting specific maturation aspects.

It was found that ascorbic acid, dexamethasone, insulin, sodium selenite, T3, and transferrin contribute to viability and more mature calcium transients and contractility, whereas replacing galactose with glucose or removing fatty acids only affected mitochondrial function but did not change intracellular calcium dynamics, impedance, or voltage-gated sodium (Nav) current parameters.

Overall, this study reveals how different medium components influence cardiomyocyte maturation, helping to replicate adult human heart conditions more accurately in the lab. The study provides a balanced medium formulation for enhancing multiple facets of hiPSC-CM maturation and establishes a powerful platform for screening novel maturation inducers.

Find the original article here: https://www.cell.com/cell-reports/fulltext/S2211-1247(24)00488-1

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